Publications by authors named "Richard J Roman"

200 Publications

Capillary Stalling: A Mechanism of Decreased Cerebral Blood Flow in AD/ADRD.

J Exp Neurol 2021 ;2(4):149-153

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are debilitating conditions that are highly associated with aging populations, especially those with comorbidities such as diabetes and hypertension. In addition to the classical pathological findings of AD, such as beta-amyloid (Aβ) accumulation and tau hyperphosphorylation, vascular dysfunction is also associated with the progression of the disease. Vascular dysfunction in AD is associated with decreased cerebral blood flow (CBF). Impaired CBF is an early and persistent symptom of AD/ADRD and is thought to be associated with deficient autoregulation and neurovascular coupling. Another recently elucidated mechanism that contributes to cerebral hypoperfusion is capillary stalling, or the temporary arrest of capillary blood flow usually precipitated by a stalled leukocyte or constriction of actin-containing capillary pericytes. Stalled capillaries are associated with decreased CBF and impaired cognitive performance. AD/ADRD are associated with chronic, low-level inflammation, which contributes to capillary stalling by increased cell adhesion molecules, circulating leukocytes, and reactive oxygen species production. Recent research has shed light on potential targets to decrease capillary stalling in AD mice. Separate inhibition of Ly6G and VEGF-A has been shown to decrease capillary stalling and increase CBF in AD mice. These results suggest that targeting stalled capillaries could influence the outcome of AD and potentially be a target for future therapies.
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http://dx.doi.org/10.33696/neurol.2.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8754422PMC
January 2021

Luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, reverses cerebrovascular dysfunction and cognitive impairments in 18-mo-old diabetic animals.

Am J Physiol Heart Circ Physiol 2022 Feb 24;322(2):H246-H259. Epub 2021 Dec 24.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved are not well understood. We previously discovered that hyperglycemia induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-mo-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reducing plasma glucose with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-mo-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage. This study demonstrates that luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, improved CBF autoregulation in association with reduced vascular oxidative stress and AGEs production in the cerebrovasculature of 18-mo-old DM rats. SGLT2i also prevented BBB leakage, impaired functional hyperemia, neurodegeneration, and cognitive impairment seen in DM rats. Luseogliflozin did not have direct constrictive effects on VSMCs and MCAs isolated from normal rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.
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http://dx.doi.org/10.1152/ajpheart.00438.2021DOI Listing
February 2022

The adducin saga: Pleiotropic genomic targets for precision medicine in human hypertension; vascular, renal, and cognitive diseases.

Physiol Genomics 2021 Dec 3. Epub 2021 Dec 3.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, United States.

Hypertension is a leading risk factor for stroke, heart disease, chronic kidney disease, vascular cognitive impairment, and Alzheimer's disease. Previous genetic studies have nominated hundreds of genes linked to hypertension and renal and cognitive diseases. Some have been advanced as candidate genes by showing that they can alter blood pressure or renal and cerebral vascular function in knockout animals; however, final validation of the causal variants and underlying mechanisms have remained elusive. This review chronicles 40 years of work, from the initial identification of adducin (ADD) as an ACTIN-binding protein suggested to increase blood pressure in Milan hypertensive rats, to the discovery of a mutation in ADD1 as a candidate gene for hypertension in rats that were subsequently linked to hypertension in man. More recently, a recessive K572Q mutation in ADD3 was identified in Fawn-Hooded Hypertensive (FHH) and Milan Normotensive (MNS) rats that develop renal disease, which is absent in resistant strains. ADD3 dimerizes with ADD1 to form functional ADD protein. The mutation in ADD3 disrupts a critical ACTIN-binding site necessary for its interactions with actin and spectrin to regulate the cytoskeleton. Studies using Add3 knockout and transgenic strains, as well as a genetic complementation study in FHH and MNS rats, confirmed that the K572Q mutation in ADD3 plays a causal role in altering the myogenic response and autoregulation of renal and cerebral blood flow, resulting in increased susceptibility to hypertension-induced renal disease and cerebral vascular and cognitive dysfunction.
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http://dx.doi.org/10.1152/physiolgenomics.00119.2021DOI Listing
December 2021

Hippocampus is more susceptible to hypoxic injury: has the Rosetta Stone of regional variation in neurovascular coupling been deciphered?

Geroscience 2021 Aug 28. Epub 2021 Aug 28.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.

Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) are associated with cerebral hypoperfusion or reductions in baseline cerebral blood flow (CBF). The neurovascular coupling (NVC) response or functional hyperemia regulates brain perfusion via a retrograde (capillary-to-arteriole) pathway by increasing regional CBF in response to local neuron activation. The hippocampus plays a significant role in spatial and non-spatial memory. Functional MRI (fMRI) has not established a solid positive correlation between hippocampal blood oxygen level-dependent (BOLD) signal and local neuronal activity. The inconsistency of NVC in the hippocampus compared to the neocortex is possibly due to anatomical and methodological difficulties to accurately detect hippocampal blood flow. A recent study reported that NVC and oxygenation are reduced in the hippocampus compared to the cortex using a novel invasive surgical approach by creating a cranial window with and without removing the neocortex. Results from these studies suggest that the hippocampus is more susceptible to hypoxic injury in pathological conditions when NVC is impaired, such as AD/ADRD, stroke, and traumatic brain injury (TBI). The Rosetta Stone of regional variation in the NVC and its significance in AD/ADRD has not been fully deciphered based on these results without addressing remaining concerns; however, we are one step closer, indeed.
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http://dx.doi.org/10.1007/s11357-021-00449-4DOI Listing
August 2021

Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE.

Clin Sci (Lond) 2021 08;135(15):1929-1944

Departments of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, U.S.A.

The accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer's disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aβ or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aβ or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood-brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.
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http://dx.doi.org/10.1042/CS20201033DOI Listing
August 2021

Traumatic brain injury induced by exposure to blast overpressure via ear canal.

Neural Regen Res 2022 Jan;17(1):115-121

Departmant of Otolaryngology and Head Neck Surgery; Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA.

Exposure to explosive shockwave often leads to blast-induced traumatic brain injury in military and civilian populations. Unprotected ears are most often damaged following exposure to blasts. Although there is an association between tympanic membrane perforation and TBI in blast exposure victims, little is known about how and to what extent blast energy is transmitted to the central nervous system via the external ear canal. The present study investigated whether exposure to blasts directed through the ear canal causes brain injury in Long-Evans rats. Animals were exposed to a single blast (0-30 pounds per square inch (psi)) through the ear canal, and brain injury was evaluated by histological and behavioral outcomes at multiple time-points. Blast exposure not only caused tympanic membrane perforation but also produced substantial neuropathological changes in the brain, including increased expression of c-Fos, induction of a profound chronic neuroinflammatory response, and apoptosis of neurons. The blast-induced injury was not limited only to the brainstem most proximal to the source of the blast, but also affected the forebrain including the hippocampus, amygdala and the habenula, which are all involved in cognitive functions. Indeed, the animals exhibited long-term neurological deficits, including signs of anxiety in open field tests 2 months following blast exposure, and impaired learning and memory in an 8-arm maze 12 months following blast exposure. These results suggest that the unprotected ear canal provides a locus for blast waves to cause TBI. This study was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center (Animal protocol# 0932E, approval date: September 30, 2016 and 0932F, approval date: September 27, 2019).
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http://dx.doi.org/10.4103/1673-5374.314311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451570PMC
January 2022

Recent Insights Into the Protective Mechanisms of Paeoniflorin in Neurological, Cardiovascular, and Renal Diseases.

J Cardiovasc Pharmacol 2021 06;77(6):728-734

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS.

Abstract: The monoterpene glycoside paeoniflorin (PF) is the principal active constituent of the traditional Chinese herbal medicines, Radix Paeoniae Alba and Radix Paeoniae Rubra, which have been used for millennia to treat cardiovascular diseases (eg, hypertension, bleeding, and atherosclerosis) and neurological ailments (eg, headaches, vertigo, dementia, and pain). Recent evidence has revealed that PF exerts inhibitory effects on inflammation, fibrosis, and apoptosis by targeting several intracellular signaling cascades. In this review, we address the current knowledge about the pharmacokinetic properties of PF and its molecular mechanisms of action. We also present results from recent preclinical studies supporting the utility of PF for the treatment of pain, cerebral ischemic injury, and neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Moreover, new evidence suggests a general protective role of PF in heart attack, diabetic kidney, and atherosclerosis. Mechanistically, PF exerts multiple anti-inflammatory actions by targeting toll-like receptor-mediated signaling in both parenchymal and immune cells (in particular, macrophages and dendritic cells). A better understanding of the molecular actions of PF may lead to the expansion of its therapeutic uses.
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http://dx.doi.org/10.1097/FJC.0000000000001021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169546PMC
June 2021

Aging diabetes, deconstructing the cerebrovascular wall.

Aging (Albany NY) 2021 04 12;13(7):9158-9159. Epub 2021 Apr 12.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

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http://dx.doi.org/10.18632/aging.202963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064220PMC
April 2021

Reversal of cerebral hypoperfusion: a novel therapeutic target for the treatment of AD/ADRD?

Geroscience 2021 04 27;43(2):1065-1067. Epub 2021 Mar 27.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are emerging global health care crises and are primarily found among aging, especially with diabetes and hypertension. However, treatments based on current understanding have not been effective. The importance of vascular contribution to AD/ADRD has been recommended by the NINDS and NIA to be a focused research area. A recent study identified that phosphatidylinositol 4,5-bisphosphate (PIP) or its analogs could reverse cerebral hypoperfusion at the neurovascular unit in AD mice. Although more studies are needed to validate if PIP analogs have sustained effects on CBF and can rescue cognitive impairment in AD/ADRD, and to elucidate and clarify whether targeting the retrograde (capillary-to-arteriole) pathway is beneficial to BBB function in AD/ADRD with poor CBF autoregulation, this finding provides exciting progress in understanding vascular contributions to AD/ADRD and suggests that reversal of cerebral hypoperfusion could be a novel therapeutic target for the treatment of AD/ADRD.
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http://dx.doi.org/10.1007/s11357-021-00357-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110616PMC
April 2021

20-HETE-promoted cerebral blood flow autoregulation is associated with enhanced pericyte contractility.

Prostaglandins Other Lipid Mediat 2021 06 19;154:106548. Epub 2021 Mar 19.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, 39216, USA. Electronic address:

We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, HET0016, but restored with 20-HETE analog WIT003. Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and were rescued by WIT003. The myogenic response of the PA was abolished in SS and was restored in SS.BN5 and SS.Cyp4a1 rats. HET0016 enhanced CBF and impaired its autoregulation in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in controlling cerebral vascular function.
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http://dx.doi.org/10.1016/j.prostaglandins.2021.106548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154705PMC
June 2021

Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke.

Int J Mol Sci 2021 Feb 19;22(4). Epub 2021 Feb 19.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca influx through TRPC6 activates the cAMP (adenosine 3',5'-cyclic monophosphate) response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of N-methyl-d-aspartate (NMDA) receptors of neurons by posttranslational means. Unresolved though, are the roles of TRPC6 channels in non-neuronal cells, such as astrocytes and endothelial cells. Moreover, TRPC6 channels may have detrimental effects on the blood-brain barrier, although their exact role in neurovascular coupling requires further investigation. This review discusses evidence-based cell-specific aspects of TRPC6 in the brain to assess the potential targets for ischemic stroke management.
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http://dx.doi.org/10.3390/ijms22042074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922996PMC
February 2021

Knockout of -Adducin Promotes N-Nitro-L-Arginine-Methyl-Ester-Induced Hypertensive Renal Injury.

J Pharmacol Exp Ther 2021 04 7;377(1):189-198. Epub 2021 Jan 7.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi

Previous studies identified a region on chromosome 1 associated with N-nitro-L-arginine methyl ester (L-NAME) hypertension-induced renal disease in fawn-hooded hypertensive (FHH) rats. This region contains a mutant -adducin () gene that impairs renal blood flow (RBF) autoregulation, but its contribution to renal injury is unknown. The present study evaluated the hypothesis that knockout (KO) of impairs the renal vasoconstrictor response to the blockade of nitric oxide synthase and enhances hypertension-induced renal injury after chronic administration of L-NAME plus a high-salt diet. The acute hemodynamic effect of L-NAME and its chronic effects on hypertension and renal injury were compared in FHH 1 (FHH 1) congenic rats (WT) expressing wild-type gene versus FHH 1 KO rats. RBF was well autoregulated in WT rats but impaired in KO rats. Acute administration of L-NAME (10 mg/kg) raised mean arterial pressure (MAP) similarly in both strains, but RBF and glomerular filtration rate (GFR) fell by 38% in WT versus 15% in KO rats. MAP increased similarly in both strains after chronic administration of L-NAME and a high-salt diet; however, proteinuria and renal injury were greater in KO rats than in WT rats. Surprisingly, RBF, GFR, and glomerular capillary pressure were 41%, 82%, and 13% higher in L-NAME-treated KO rats than in WT rats. Hypertensive KO rats exhibited greater loss of podocytes and glomerular nephrin expression and increased interstitial fibrosis than in WT rats. These findings indicate that loss of ADD3 promotes L-NAME-induced renal injury by altering renal hemodynamics and enhancing the transmission of pressure to glomeruli. SIGNIFICANCE STATEMENT: A mutation in the -adducin () gene in fawn-hooded hypertensive rats that impairs autoregulation of renal blood flow is in a region of rat chromosome 1 homologous to a locus on human chromosome 10 associated with diabetic nephropathy. The present results indicate that loss of ADD3 enhanced N-nitro-L-arginine methyl ester-induced hypertensive renal injury by altering the transmission of pressure to the glomerulus.
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http://dx.doi.org/10.1124/jpet.120.000408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051517PMC
April 2021

Genetic susceptibility of hypertension-induced kidney disease.

Physiol Rep 2021 01;9(1):e14688

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Hypertension is the second leading cause of end-stage renal disease (ESRD) after diabetes mellitus. The significant differences in the incidence of hypertensive ESRD between different patient populations worldwide and patients with and without family history indicate that genetic determinants play an important role in the onset and progression of this disease. Recent studies have identified genetic variants and pathways that may contribute to the alteration of renal function. Mechanisms involved include affecting renal hemodynamics (the myogenic and tubuloglomerular feedback responses); increasing the production of reactive oxygen species in the tubules; altering immune cell function; changing the number, structure, and function of podocytes that directly cause glomerular damage. Studies with hypertensive animal models using substitution mapping and gene knockout strategies have identified multiple candidate genes associated with the development of hypertension and subsequent renal injury. Genome-wide association studies have implicated genetic variants in UMOD, MYH9, APOL-1, SHROOM3, RAB38, and DAB2 have a higher risk for ESRD in hypertensive patients. These findings provide genetic evidence of potential novel targets for drug development and gene therapy to design individualized treatment of hypertension and related renal injury.
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http://dx.doi.org/10.14814/phy2.14688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772938PMC
January 2021

Duration and magnitude of bidirectional fluctuation in blood pressure: the link between cerebrovascular dysfunction and cognitive impairment following spinal cord injury.

J Neurobiol Physiol 2020 ;2(1):15-18

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Individuals with spinal cord injury (SCI) have a significantly increased risk for cognitive impairment that is associated with cerebrovascular remodeling and endothelial dysfunction. The sub-acute stage following high thoracic SCI is characterized by increased fibrosis and stiffness of cerebral arteries. However, a more prolonged duration after SCI exacerbates cerebrovascular injury by damaging endothelium. Endothelial dysfunction is associated with reduced expression of transient receptor potential cation channel 4 that mediates the production of nitric oxide and epoxyeicosatrienoic acids following shear stress and the response to carbachol and other endothelium-dependent vasodilators. Reduced expression of CD31 in cerebral arteries also suggests the loss of endothelial cell integrity following chronic SCI. Repetitively transient hypertension and intermittent hypotension contribute to cerebrovascular endothelial dysfunction in the animals with a sub-acute stage of high thoracic SCI. The increase in vascular remodeling and endothelial dysfunction ultimately reduce cerebral blood flow, which promotes cerebral hypoperfusion and cognitive dysfunction in the chronic phase of SCI. In conclusion, the duration and magnitude of fluctuations in blood pressure after SCI play a vital role in the onset and progress of cerebrovascular dysfunction, which promotes the development of cognitive impairment.
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http://dx.doi.org/10.46439/neurobiology.2.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739907PMC
January 2020

Role of γ-adducin in actin cytoskeleton rearrangements in podocyte pathophysiology.

Am J Physiol Renal Physiol 2021 01 14;320(1):F97-F113. Epub 2020 Dec 14.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.

We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the fawn-hooded hypertensive (FHH) rat is caused, at least in part, by a mutation in γ-adducin (ADD3) that attenuates renal vascular function. The present study explored whether contributes to the modulation of podocyte structure and function using FHH and FHH. transgenic rats. The expression of ADD3 on the membrane of primary podocytes isolated from FHH was reduced compared with FHH. transgenic rats. We found that F-actin nets, which are typically localized in the lamellipodia, replaced unbranched stress fibers in conditionally immortalized mouse podocytes transfected with Dicer-substrate short interfering RNA (DsiRNA) and primary podocytes isolated from FHH rats. There were increased F/G-actin ratios and expression of the Arp2/3 complexes throughout FHH podocytes in association with reduced synaptopodin and RhoA but enhanced Rac1 and CDC42 expression in the renal cortex, glomeruli, and podocytes of FHH rats. The expression of nephrin at the slit diaphragm and the levels of focal adhesion proteins integrin-α and integrin-β were decreased in the glomeruli of FHH rats. Cell migration was enhanced and adhesion was reduced in podocytes of FHH rats as well as in immortalized mouse podocytes transfected with DsiRNA. Mean arterial pressures were similar in FHH and FHH. transgenic rats at 16 wk of age; however, FHH rats exhibited enhanced proteinuria associated with podocyte foot process effacement. These results demonstrate that reduced ADD3 function in FHH rats alters baseline podocyte pathophysiology by rearrangement of the actin cytoskeleton at the onset of proteinuria in young animals.
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http://dx.doi.org/10.1152/ajprenal.00423.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847051PMC
January 2021

Reduced pericyte and tight junction coverage in old diabetic rats are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction.

Am J Physiol Heart Circ Physiol 2021 02 11;320(2):H549-H562. Epub 2020 Dec 11.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.

Diabetes mellitus (DM) is one of the primary pathological factors that contributes to aging-related cognitive impairments, but the underlying mechanisms remain unclear. We recently reported that old DM rats exhibited impaired myogenic responses of the cerebral arteries and arterioles, poor cerebral blood flow autoregulation, enhanced blood-brain barrier (BBB) leakage, and cognitive impairments. These changes were associated with diminished vascular smooth muscle cell contractile capability linked to elevated reactive oxygen species (ROS) and reduced ATP production. In the present study, using a nonobese T2DN DM rat, we isolated parenchymal arterioles (PAs), cultured cerebral microvascular pericytes, and examined whether cerebrovascular pericyte in DM is damaged and whether pericyte dysfunction may play a role in the regulation of cerebral hemodynamics and BBB integrity. We found that ROS and mitochondrial superoxide production were elevated in PAs isolated from old DM rats and in high glucose (HG)-treated α-smooth muscle actin-positive pericytes. HG-treated pericytes displayed decreased contractile capability in association with diminished mitochondrial respiration and ATP production. Additionally, the expression of advanced glycation end products, transforming growth factor-β, vascular endothelial growth factor, and fibronectin were enhanced, but claudin 5 and integrin β1 was reduced in the brain of old DM rats and HG-treated pericytes. Further, endothelial tight junction and pericyte coverage on microvessels were reduced in the cortex of old DM rats. These results demonstrate our previous findings that the impaired cerebral hemodynamics and BBB leakage and cognitive impairments in the same old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction. This study demonstrates that the loss of contractile capability in pericytes in diabetes is associated with enhanced ROS and reduced ATP production. Enhanced advanced glycation end products (AGEs) in diabetes accompany with reduced pericyte and endothelial tight junction coverage in the cortical capillaries of old diabetic rats. These results suggest our previous findings that the impaired cerebral hemodynamics, BBB leakage, and cognitive impairments in old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction.
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http://dx.doi.org/10.1152/ajpheart.00726.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082790PMC
February 2021

Increased Levels of Renal Lysophosphatidic Acid in Rodent Models with Renal Disease.

J Pharmacol Exp Ther 2021 02 4;376(2):240-249. Epub 2020 Dec 4.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan

Lysophosphatidic acid (LPA) is a bioactive lipid mediator that has been implicated in the pathophysiology of kidney disease. However, few studies have attempted to measure changes in the levels of various LPA species in the kidney after the development of renal disease. The present study measured the renal LPA levels during the development of kidney disease in rat models of hypertension, diabetes, and obstructive nephropathy using liquid chromatography/mass spectrometry/mass spectrometry. LPA levels (sum of 16:0, 18:0, 18:1, 18:2, and 20:4 LPA) were higher in the renal cortex of hypertensive Dahl salt-sensitive (Dahl S) rats fed a high-salt diet than those in normotensive rats fed a low-salt diet (296.6 ± 22.9 vs. 196.3 ± 8.5 nmol/g protein). LPA levels were elevated in the outer medulla of the kidney of streptozotocin-induced type 1 diabetic Dahl S rats compared with control rats (624.6 ± 129.5 vs. 318.8 ± 17.1 nmol/g protein). LPA levels were also higher in the renal cortex of 18-month-old, type 2 diabetic nephropathy (T2DN) rats with more severe renal injury than in 6-month-old T2DN rats (184.9 ± 20.9 vs. 116.9 ± 6.0 nmol/g protein). LPA levels also paralleled the progression of renal fibrosis in the renal cortex of Sprague-Dawley rats after unilateral ureteral obstruction (UUO). Administration of an LPA receptor antagonist, Ki16425, reduced the degree of renal fibrosis in UUO rats. These results suggest that the production of renal LPA increases during the development of renal injury and contributes to renal fibrosis. SIGNIFICANCE STATEMENT: The present study reveals that the lysophosphatidic acid (LPA) levels increase in the kidney in rat models of hypertension, diabetes, and obstructive nephropathy, and administration of an LPA receptor antagonist attenuates renal fibrosis. Therapeutic approaches that target the formation or actions of renal LPA might be renoprotective and have therapeutic potential.
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http://dx.doi.org/10.1124/jpet.120.000353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841420PMC
February 2021

Eicosanoid Profiles in the Vitreous Humor of Patients with Proliferative Diabetic Retinopathy.

Int J Mol Sci 2020 Oct 9;21(20). Epub 2020 Oct 9.

Department of Ophthalmology, University of Florida College of Medicine, Gainesville, FL 32610, USA.

Proliferative diabetic retinopathy is a potentially blinding sequela of uncontrolled diabetes that involves a complex interaction of pro-angiogenic and inflammatory pathways. In this study, we compared the levels of pro-angiogenic arachidonic acid-derived mediators in human vitreous humor obtained from eyes with high-risk proliferative diabetic retinopathy versus controls. The results indicated that lipoxygenase and cytochrome P450-derived eicosanoids were elevated (5-HETE, 12-HETE, 20-HETE, and 20-COOH-AA) and there appeared to be no differences in levels measured in eyes with tractional retinal detachments versus those without. These results provide further insight into the pathogenesis of this disease and for the development of future potential therapeutic agents that target arachidonic acid metabolites to treat diabetic retinopathy.
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http://dx.doi.org/10.3390/ijms21207451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589012PMC
October 2020

20-HETE Enzymes and Receptors in the Neurovascular Unit: Implications in Cerebrovascular Disease.

Front Neurol 2020 4;11:983. Epub 2020 Sep 4.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, United States.

20-HETE is a potent vasoconstrictor that is implicated in the regulation of blood pressure, cerebral blood flow and neuronal death following ischemia. Numerous human genetic studies have shown that inactivating variants in the cytochrome P450 enzymes that produce 20-HETE are associated with hypertension, stroke and cerebrovascular disease. However, little is known about the expression and cellular distribution of the cytochrome P450A enzymes (CYP4A) that produce 20-HETE or the newly discovered 20-HETE receptor (GPR75) in the brain. The present study examined the cell types and regions in the rat forebrain that express CYP4A and GPR75. Brain tissue slices from Sprague Dawley (SD), Dahl Salt-Sensitive (SS) and CYP4A1 transgenic rat strains, as well as cultured human cerebral pericytes and cerebral vascular smooth muscle cells, were analyzed by fluorescent immunostaining. Tissue homogenates from these strains and cultured cells were examined by Western blot. In the cerebral vasculature, CYP4A and GPR75 were expressed in endothelial cells, vascular smooth muscle cells and the glial limiting membrane of pial arteries and penetrating arterioles but not in the endothelium of capillaries. CYP4A, but not GPR75, was expressed in astrocytes. CYP4A and GPR75 were both expressed in a subpopulation of pericytes on capillaries. The diameters of capillaries were significantly decreased at the sites of first and second-order pericytes that expressed CYP4A. Capillary diameters were unaffected at the sites of other pericytes that did not express CYP4A. These findings implicate 20-HETE as a paracrine mediator in various components of the neurovascular unit and are consistent with 20-HETE's emerging role in the regulation of cerebral blood flow, blood-brain barrier integrity, the pathogenesis of stroke and the vascular contributions to cognitive impairment and dementia. Moreover, this study highlights GPR75 as a potential therapeutic target for the treatment of these devastating conditions.
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http://dx.doi.org/10.3389/fneur.2020.00983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499024PMC
September 2020

Impaired renal hemodynamics and glomerular hyperfiltration contribute to hypertension-induced renal injury.

Am J Physiol Renal Physiol 2020 10 24;319(4):F624-F635. Epub 2020 Aug 24.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.

Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1 congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1 KO (KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in KO rats. The degree of renal injury was greater in KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive KO rats.
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http://dx.doi.org/10.1152/ajprenal.00239.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642882PMC
October 2020

Aging exacerbates impairments of cerebral blood flow autoregulation and cognition in diabetic rats.

Geroscience 2020 10 21;42(5):1387-1410. Epub 2020 Jul 21.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.

Diabetes mellitus (DM) is a leading risk factor for aging-related dementia; however, the underlying mechanisms are not well understood. The present study, utilizing a non-obese T2DN diabetic model, demonstrates that the myogenic response of the middle cerebral artery (MCA) and parenchymal arteriole (PA) and autoregulation of cerebral blood flow (CBF) in the surface and deep cortex were impaired at both young and old ages. The impaired CBF autoregulation was more severe in old than young DM rats, and in the deep than the surface cortex. The myogenic tone of the MCA was enhanced at perfusion pressure in the range of 40-100 mmHg in young DM rats but was reduced at 140-180 mmHg in old DM rats. No change of the myogenic tone of the PA was observed in young DM rats, whereas it was significantly reduced at 30-60 mmHg in old DM rats. Old DM rats had enhanced blood-brain barrier (BBB) leakage and neurodegeneration, reduced vascular density, tight junction, and pericyte coverage on cerebral capillaries in the CA3 region in the hippocampus. Additionally, DM rats displayed impaired functional hyperemia and spatial learning and short- and long-term memory at both young and old ages. Old DM rats had impaired non-spatial short-term memory. These results revealed that impaired CBF autoregulation and enhanced BBB leakage plays an essential role in the pathogenesis of age- and diabetes-related dementia. These findings will lay the foundations for the discovery of anti-diabetic therapies targeting restoring CBF autoregulation to prevent the onset and progression of dementia in elderly DM.
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http://dx.doi.org/10.1007/s11357-020-00233-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525432PMC
October 2020

Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature.

J Neurotrauma 2020 09 1;37(18):1963-1970. Epub 2020 Jul 1.

International Collaboration on Repair Discoveries, Vancouver, British Columbia, Canada.

Individuals living with chronic spinal cord injury (SCI) often exhibit impairments in cognitive function, which impede their rehabilitation and transition into the community. Although a number of clinical studies have demonstrated the impact of impaired cardiovascular control on cognitive impairment, the mechanistic understanding of this deleterious relationship is still lacking. The present study investigates whether chronic disruption of cardiovascular control following experimental SCI results in cerebrovascular decline and vascular cognitive impairment. Fourteen weeks following a high thoracic SCI (at the third thoracic segment), rats were subjected to a battery of and physiological assessments, cognitive-behavioral tests, and immunohistochemical approaches to investigate changes in cerebrovascular structure and function in the middle cerebral artery (MCA). We show that in the MCA of rats with SCI, there is a 55% (SCI vs. control: 13.4 ± 1.9% vs. 29.63 ± 2.8%, respectively) reduction in the maximal vasodilator response to carbachol, which is associated with reduced expression of endothelial marker cluster of differentiation 31 (CD31) and transient receptor potential cation channel 4 (TRPV 4) channels. Compared with controls, MCAs in rats with SCI were found to have 50% (SCI vs. control: 1.5 ± 0.2 vs. 1 ± 0.1 a.u., respectively) more collagen 1 in the media of vascular wall and 37% (SCI vs. control: 30.5 ± 2.9% vs. 42.0 ± 4.0%, respectively) less distensibility at physiological intraluminal pressure. Further, the cerebral blood flow (CBF) in the hippocampus was reduced by 32% in the SCI group (SCI vs. control: 44.3 ± 4.5 mL/100 g/min vs. 65.0 ± 7.2 mL/100 g/min, respectively) in association with impairment of short-term memory based on a novel object recognition test. There were no changes in the sympathetic innervation of the vasculature and passive structure in the SCI group. Chronic experimental SCI is associated with structural alterations and endothelial dysfunction in cerebral arteries that likely contribute to significantly reduced CBF and vascular cognitive impairment.
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http://dx.doi.org/10.1089/neu.2019.6913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470217PMC
September 2020

Sex differences in the structure and function of rat middle cerebral arteries.

Am J Physiol Heart Circ Physiol 2020 05 27;318(5):H1219-H1232. Epub 2020 Mar 27.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.

Epidemiological studies demonstrate that there are sex differences in the incidence, prevalence, and outcomes of cerebrovascular disease (CVD). The present study compared the structure and composition of the middle cerebral artery (MCA), neurovascular coupling, and cerebrovascular function and cognition in young Sprague-Dawley (SD) rats. Wall thickness and the inner diameter of the MCA were smaller in females than males. Female MCA exhibited less vascular smooth muscle cells (VSMCs), diminished contractile capability, and more collagen in the media, and a thicker internal elastic lamina with fewer fenestrae compared with males. Female MCA had elevated myogenic tone, lower distensibility, and higher wall stress. The stress/strain curves shifted to the left in female vessels compared with males. The MCA of females failed to constrict compared with a decrease of 15.5 ± 1.9% in males when perfusion pressure was increased from 40 to 180 mmHg. Cerebral blood flow (CBF) rose by 57.4 ± 4.4 and 30.1 ± 3.1% in females and males, respectively, when perfusion pressure increased from 100 to 180 mmHg. The removal of endothelia did not alter the myogenic response in both sexes. Functional hyperemia responses to whisker-barrel stimulation and cognition examined with an eight-arm water maze were similar in both sexes. These results demonstrate that there are intrinsic structural differences in the MCA between sexes, which are associated with diminished myogenic response and CBF autoregulation in females. The structural differences do not alter neurovascular coupling and cognition at a young age; however, they might play a role in the development of CVD after menopause. Using perfusion fixation of the middle cerebral artery (MCA) in calcium-free solution at physiological pressure and systematically randomly sampling the sections prepared from the same M2 segments of MCA, we found that there are structural differences that are associated with altered cerebral blood flow (CBF) autoregulation but not neurovascular coupling and cognition in young, healthy Sprague-Dawley (SD) rats. Understanding the intrinsic differences in cerebrovascular structure and function in males and females is essential to develop new pharmaceutical treatments for cerebrovascular disease (CVD).
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http://dx.doi.org/10.1152/ajpheart.00722.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346534PMC
May 2020

Accelerated cerebral vascular injury in diabetes is associated with vascular smooth muscle cell dysfunction.

Geroscience 2020 04 12;42(2):547-561. Epub 2020 Mar 12.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.

Individuals with diabetes are more susceptible to cerebral vascular aging. However, the underlying mechanisms are not well elucidated. The present study examined whether the myogenic response of the middle cerebral artery (MCA) is impaired in diabetic rats due to high glucose (HG)-induced cerebral vascular smooth muscle cell (CVSMC) dysfunction, and whether this is associated with ATP depletion and changes in mitochondrial dynamics and membrane potential. The diameters of the MCA of diabetic rats increased to 135.3 ± 11.3% when perfusion pressure was increased from 40 to 180 mmHg, while it fell to 85.1 ± 3.1% in non-diabetic controls. The production of ROS and mitochondrial-derived superoxide were enhanced in cerebral arteries of diabetic rats. Levels of mitochondrial superoxide were significantly elevated in HG-treated primary CVSMCs, which was associated with decreased ATP production, mitochondrial respiration, and membrane potential. The expression of OPA1 was reduced, and MFF was elevated in HG-treated CVSMCs in association with fragmented mitochondria. Moreover, HG-treated CVSMCs displayed lower contractile and proliferation capabilities. These results demonstrate that imbalanced mitochondrial dynamics (increased fission and decreased fusion) and membrane depolarization contribute to ATP depletion in HG-treated CVSMCs, which promotes CVSMC dysfunction and may play an essential role in exacerbating the impaired myogenic response in the cerebral circulation in diabetes and accelerating vascular aging.
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http://dx.doi.org/10.1007/s11357-020-00179-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205935PMC
April 2020

A Mutation in -Adducin Impairs Autoregulation of Renal Blood Flow and Promotes the Development of Kidney Disease.

J Am Soc Nephrol 2020 04 6;31(4):687-700. Epub 2020 Feb 6.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;

Background: The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for -adducin (ADD3), a cytoskeletal protein encoded by .

Methods: We investigated renal vascular function and and the susceptibility to CKD in rats with wild-type or mutated and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats.

Results: This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats-a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from transgenic rats, those from FHH rats had elevated membrane expression of BK and BK channel current. FHH and knockout rats exhibited impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension.

Conclusions: This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.
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http://dx.doi.org/10.1681/ASN.2019080784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191921PMC
April 2020

Influence of dual-specificity protein phosphatase 5 on mechanical properties of rat cerebral and renal arterioles.

Physiol Rep 2020 01;8(2):e14345

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.

We recently reported that KO of Dual-specificity protein phosphatase 5 (Dusp5) enhances myogenic reactivity and blood flow autoregulation in the cerebral and renal circulations in association with increased levels of pPKC and pERK1/2 in the cerebral and renal arteries and arterioles. In the kidney, hypertension-related renal damage was significantly attenuated in Dusp5 KO rats. Elevations in pPKC and pERK1/2 promote calcium influx in VSMC and facilitate vasoconstriction. However, whether DUSP5 plays a role in altering the passive mechanical properties of cerebral and renal arterioles has never been investigated. In this study, we found that KO of Dusp5 did not alter body weights, kidney and brain weights, plasma glucose, and Hb levels. The expression of pERK is higher in the nucleus of primary VSMC isolated from Dusp5 KO rats. Dusp5 KO rats exhibited eutrophic vascular hypotrophy with smaller intracerebral parenchymal arterioles and renal interlobular arterioles without changing the wall-to-lumen ratios. These arterioles from Dusp5 KO rats displayed higher myogenic tones, better distensibility, greater compliance, and less stiffness compared with arterioles from WT control rats. VSMC of Dusp5 KO rats exhibited a stronger contractile capability. These results demonstrate, for the first time, that DUSP5 contributes to the regulation of the passive mechanical properties of cerebral and renal arterioles and provide new insights into the role of DUSP5 in vascular function, cancer, stroke, and other cardiovascular diseases.
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http://dx.doi.org/10.14814/phy2.14345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971329PMC
January 2020

The angiotensin II type I receptor contributes to impaired cerebral blood flow autoregulation caused by placental ischemia in pregnant rats.

Biol Sex Differ 2019 12 11;10(1):58. Epub 2019 Dec 11.

Department of Physiology & Biophysics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.

Background: Placental ischemia and hypertension, characteristic features of preeclampsia, are associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. However, the factors that contribute to these cerebral abnormalities are not clear. Several lines of evidence suggest that angiotensin II can impact cerebrovascular function; however, the role of the renin angiotensin system in cerebrovascular function during placental ischemia has not been examined. We tested whether the angiotensin type 1 (AT1) receptor contributes to impaired CBF autoregulation in pregnant rats with placental ischemia caused by surgically reducing uterine perfusion pressure.

Methods: Placental ischemic or sham operated rats were treated with vehicle or losartan from gestational day (GD) 14 to 19 in the drinking water. On GD 19, we assessed CBF autoregulation in anesthetized rats using laser Doppler flowmetry.

Results: Placental ischemic rats had impaired CBF autoregulation that was attenuated by treatment with losartan. In addition, we examined whether an agonistic autoantibody to the AT1 receptor (AT1-AA), reported to be present in preeclamptic women, contributes to impaired CBF autoregulation. Purified rat AT1-AA or vehicle was infused into pregnant rats from GD 12 to 19 via mini-osmotic pumps after which CBF autoregulation was assessed. AT1-AA infusion impaired CBF autoregulation but did not affect brain water content.

Conclusions: These results suggest that the impaired CBF autoregulation associated with placental ischemia is due, at least in part, to activation of the AT1 receptor and that the RAS may interact with other placental factors to promote cerebrovascular changes common to preeclampsia.
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http://dx.doi.org/10.1186/s13293-019-0275-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907203PMC
December 2019

DMOG, a Prolyl Hydroxylase Inhibitor, Increases Hemoglobin Levels without Exacerbating Hypertension and Renal Injury in Salt-Sensitive Hypertensive Rats.

J Pharmacol Exp Ther 2020 02 4;372(2):166-174. Epub 2019 Dec 4.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (S.K., R.J.R.); and Pharmacology Laboratories (S.K., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.

Prolyl hydroxylase (PHD) inhibitors are being developed as alternatives to recombinant human erythropoietin (rHuEPO) for the treatment of anemia in patients with chronic kidney disease (CKD). However, the effects of PHD inhibitors and rHuEPO on blood pressure and CKD in animal models susceptible to hypertension and nephropathy have not been studied. The present study compared the effects of dimethyloxaloylglycine (DMOG), a PHD inhibitor, and rHuEPO on the development of hypertension and renal injury in Dahl salt-sensitive rats fed an 8% salt diet for 3 weeks. DMOG and rHuEPO were equally effective at raising hemoglobin levels. Systolic blood pressure rose to a greater extent in rHuEPO-treated rats (267 ± 10 vs. 226 ± 4 mm Hg) than in rats given DMOG (189 ± 8 mm Hg). Urinary protein excretion increased to 568 ± 54 versus 353 ± 25 mg/day in rats treated with rHuEPO and vehicle; however, it only rose to 207 ± 21 mg/day in rats receiving DMOG. DMOG significantly attenuated the degree of glomerulosclerosis and renal interstitial fibrosis as compared with that in vehicle and rHuEPO-treated rats. This was associated with lower renal levels of monocyte chemoattractant protein-1 and interleukin-1 and increased vascular endothelial growth factor expression in cortex and medulla. These results indicate that DMOG and rHuEPO are equally effective in increasing hemoglobin levels in Dahl S rats; however, rHuEPO aggravates hypertension and renal injury, whereas DMOG has marked renoprotective effects. These results suggest that PHD inhibitors may have a therapeutic advantage for the treatment of anemia in CKD. SIGNIFICANCE STATEMENT: Prolyl hydroxylase (PHD) inhibitors are in phase 3 clinical trials as alternatives to recombinant human erythropoietin (rHuEPO) for the treatment of anemia in chronic kidney disease (CKD). The present study reveals that dimethyloxaloylglycine (DMOG), a PHD inhibitor, and rHuEPO are equally effective in increasing hemoglobin levels in Dahl S rats; however, rHuEPO aggravated hypertension and renal injury, whereas DMOG attenuated the development of hypertension and prevented renal injury. PHD inhibitors may provide a safer therapeutic option for the treatment of anemia in CKD.
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http://dx.doi.org/10.1124/jpet.119.262782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978707PMC
February 2020

Conflicting Roles of 20-HETE in Hypertension and Stroke.

Int J Mol Sci 2019 Sep 11;20(18). Epub 2019 Sep 11.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Hypertension is the most common modifiable risk factor for stroke, and understanding the underlying mechanisms of hypertension and hypertension-related stroke is crucial. 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE), which plays an important role in vasoconstriction, autoregulation, endothelial dysfunction, angiogenesis, inflammation, and blood-brain barrier integrity, has been linked to hypertension and stroke. 20-HETE can promote hypertension by potentiating the vascular response to vasoconstrictors; it also can reduce blood pressure by inhibition of sodium transport in the kidney. The production of 20-HETE is elevated after the onset of both ischemic and hemorrhagic strokes; on the other hand, subjects with genetic variants in and that reduce 20-HETE production are more susceptible to stroke. This review summarizes recent genetic variants in and influencing 20-HETE production and discusses the role of 20-HETE in hypertension and the susceptibility to the onset, progression, and prognosis of ischemic and hemorrhagic strokes.
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http://dx.doi.org/10.3390/ijms20184500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770042PMC
September 2019

Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury.

J Pharmacol Exp Ther 2019 08 22;370(2):206-217. Epub 2019 May 22.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center. Jackson, Mississippi (C.Z., X.H., S.R.M., H.Z., S.W., Y.G., W.G., J.M.W., R.J.R., F.F.); Department of Urology, Zhongshan Hospital, Fudan University. Shanghai, China (C.Z., W.G.); and Department of Physiology, Medical College of Wisconsin. Milwaukee, Wisconsin (A.M.G.)

Dual-specificity protein phosphatase 5 (DUSP5) is a member of the tyrosine-threonine phosphatase family with the ability to dephosphorylate and inactivate extracellular signal-related kinase (ERK). The present study investigates whether knockout (KO) of improves renal hemodynamics and protects against hypertension-induced renal injury. The renal expression of DUSP5 was reduced, and the levels of phosphorylated (p) ERK1/2 and p-protein kinase C (PKC) were elevated in the KO rats. KO of enhanced the myogenic tone of the renal afferent arteriole and interlobular artery in vitro with or without induction of deoxycorticosterone acetate-salt hypertension. Inhibition of ERK1/2 and PKC diminished the myogenic response to a greater extent in KO rats. Autoregulation of renal blood flow was significantly impaired in hypertensive wild-type (WT) rats but remained intact in KO animals. Proteinuria was markedly decreased in hypertensive KO versus WT rats. The degree of glomerular injury was reduced, and the expression of nephrin in the glomerulus was higher in hypertensive KO rats. Renal fibrosis and medullary protein cast formation were attenuated in hypertensive KO rats in association with decreased expression of monocyte chemoattractant protein 1, transforming growth factor-1, matrix metalloproteinase (MMP) 2, and MMP9. These results indicate that KO of protects against hypertension-induced renal injury, at least in part, by maintaining the myogenic tone of the renal vasculature and extending the range of renal blood flow autoregulation to higher pressures, which diminish glomerular injury, protein cast formation, macrophage infiltration, and epithelial-mesenchymal transformation in the kidney. SIGNIFICANCE STATEMENT: Dual-specificity protein phosphatase 5 (DUSP) is a tyrosine-threonine phosphatase that inactivates extracellular signal-related kinase (ERK). We previously reported that knockout (KO) of enhanced the myogenic response and autoregulation in the cerebral circulation. The present study investigates whether KO of DUSP5 improves renal hemodynamics and protects against hypertension-induced renal injury. Downregulation of DUSP5 enhanced the myogenic tone of renal arteriole and artery and autoregulation of renal blood flow in association with reduced proteinuria, glomerular injury, and interstitial fibrosis after the induction of hypertension. Inhibition of ERK1/2 and protein kinase C diminished the myogenic response to a greater extent in KO rats. These results suggest that DUSP5 might be a viable drug target for the treatment of hypertension nephropathy.
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http://dx.doi.org/10.1124/jpet.119.258954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636243PMC
August 2019
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