Publications by authors named "Kenneth Bernstein"

105 Publications

Local and Downstream Actions of Proximal Tubule Angiotensin II Signaling on Sodium Transporters in the Mouse Nephron.

Am J Physiol Renal Physiol 2021 05 31. Epub 2021 May 31.

Medicine, Oregon Health & Science University, United States

The renal nephron consists of a series of distinct cell types which function in concert to maintain fluid and electrolyte balance and blood pressure. The renin angiotensin system (RAS) is central to sodium and volume balance. We aimed to determine how loss of angiotensin II signaling in the proximal tubule (PT), which reabsorbs the bulk of filtered sodium and volume, impacts solute transport throughout the nephron. We hypothesized that proximal tubule (PT) RAS disruption would not only depress PT sodium transporters, but also impact downstream Na transporters. Utilizing a mouse model in which the type 1a angiotensin receptor (AT1aR) is deleted specifically within the PT (AT1aR PTKO), we profiled the abundance of sodium transporters, channels, and claudins along the nephron. Absence of PT AT1aR signaling was associated with lower abundance of PT transporters (NHE3, NBCe2 and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated NKCC2, medullary Na,K-ATPase, phosphorylated NCC and claudin 7) versus controls. However, transport activities of NKCC2 and NCC (assessed with diuretics) were similar between groups in order to maintain electrolyte balance. Together, these results demonstrate the primary impact of angiotensin II regulation on sodium reabsorption in PT at baseline and the associated influence on downstream Na transporters, highlighting the ability of the nephron to integrate sodium transport along the nephron to maintain homeostasis.
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http://dx.doi.org/10.1152/ajprenal.00014.2021DOI Listing
May 2021

Hippocampal sparing in patients receiving radiosurgery for ≥25 brain metastases.

Radiother Oncol 2021 May 27;161:65-71. Epub 2021 May 27.

Department of Neurosurgery, NYU Grossman School of Medicine, New York, USA; Brain and Spine Tumor Center, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, USA; Department of Radiation Oncology, NYU Grossman School of Medicine, New York, USA.

Purpose/objectives: To report our dosimetric analysis of the hippocampi (HC) and the incidence of perihippocampal tumor location in patients with ≥25 brain metastases who received stereotactic radiosurgery (SRS) in single or multiple sessions.

Materials/methods: Analysis of our prospective registry identified 89 patients treated with SRS for ≥25 brain metastases. HC avoidance regions (HA-region) were created on treatment planning MRIs by 5 mm expansion of HC. Doses from each session were summed to calculate HC dose. The distribution of metastases relative to the HA-region and the HC was analyzed.

Results: Median number of tumors irradiated per patient was 33 (range 25-116) in a median of 3 (range1-12) sessions. Median bilateral HC D (D), D, D, D, and D (Gy) was 1.88, 3.94, 3.62, 16.6, and 3.97 for all patients, and 1.43, 2.99, 2.88, 5.64, and 3.07 for patients with tumors outside the HA-region. Multivariate linear regression showed that the median HC D, D, and D were significantly correlated with the tumor number and tumor volume (p < 0.001). Of the total 3059 treated tumors, 83 (2.7%) were located in the HA-region in 57% evaluable patients; 38 tumors (1.2%) abutted or involved the HC itself.

Conclusions: Hippocampal dose is higher in patients with tumors in the HA-region; however, even for patients with a high burden of intracranial disease and tumors located in the HA-regions, SRS affords hippocampal sparing. This is particularly relevant in light of our finding of eventual perihippocampal metastases in more than half of our patients.
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http://dx.doi.org/10.1016/j.radonc.2021.05.019DOI Listing
May 2021

Stereotactic Radiosurgery for Differentiated Thyroid Cancer Brain Metastases: An International, Multicenter Study.

Thyroid 2021 May 11. Epub 2021 May 11.

Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.

Brain metastases (BM) from differentiated thyroid cancer are rare. Stereotactic radiosurgery (SRS) is commonly used for the treatment of BMs; however, the experience with SRS for thyroid cancer BMs remains limited. The goal of this international, multi-centered study was to evaluate the efficacy and safety of SRS for thyroid cancer BMs. From 10 institutions participating in the International Radiosurgery Research Foundation, we pooled patients with established papillary or follicular thyroid cancer diagnosis who underwent SRS for histologically confirmed or radiologically suspected BMs. We investigated patient overall survival (OS), local tumor control, and adverse radiation events (AREs). We studied 42 (52% men) patients who underwent SRS for 122 papillary (83%) or follicular (17%) thyroid cancer BMs. The mean age at SRS was 59.86 ± 12.69 years. The mean latency from thyroid cancer diagnosis to SRS for BMs was 89.05 ± 105.49 months. The median number of BMs per patient was 2 (range: 1-10 BMs). The median SRS treatment volume was 0.79 cm (range: 0.003-38.18 cm), and the median SRS prescription dose was 20 Gy (range: 8-24 Gy). The median survival after SRS for BMs was 14 months (range: 3-58 months). The OS was significantly shorter in patients harboring ≥2 BMs, when compared with patients with one BM (Log-rank = 5.452,  = 0.02). Two or more BMs (odds ratio [OR] = 3.688; confidence interval [CI]: 1.143-11.904;  = 0.03) and lower Karnofsky performance score at the time of SRS (OR = 0.807; CI: 0.689-0.945;  = 0.008) were associated with shorter OS. During post-SRS imaging follow-up of 25.21 ± 30.49 months, local failure (progression and/or radiation necrosis) of BMs treated with SRS was documented in five (4%) BMs at 7.2 ± 7.3 months after the SRS. At the last imaging follow-up, the majority of patients with available imaging data had stable intracranial disease (33%) or achieved complete (26%) or partial (24%) response. There were no clinical AREs. Post-SRS peritumoral T2/fluid attenuated inversion recovery signal hyperintensity was noted in 7% BMs. The SRS allows durable local control of papillary and follicular thyroid cancer BMs in the vast majority of patients. Higher number of BMs and worse functional status at the time of SRS are associated with shorter OS in patients with thyroid cancer BMs. The SRS is safe and is associated with a low risk of AREs.
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http://dx.doi.org/10.1089/thy.2020.0947DOI Listing
May 2021

Novel roles of the renal angiotensin-converting enzyme.

Mol Cell Endocrinol 2021 06 26;529:111257. Epub 2021 Mar 26.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

The observation that all components of the renin angiotensin system (RAS) are expressed in the kidney and the fact that intratubular angiotensin (Ang) II levels greatly exceed the plasma concentration suggest that the synthesis of renal Ang II occurs independently of the circulating RAS. One of the main components of this so-called intrarenal RAS is angiotensin-converting enzyme (ACE). Although the role of ACE in renal disease is demonstrated by the therapeutic effectiveness of ACE inhibitors in treating several conditions, the exact contribution of intrarenal versus systemic ACE in renal disease remains unknown. Using genetically modified mouse models, our group demonstrated that renal ACE plays a key role in the development of several forms of hypertension. Specifically, although ACE is expressed in different cell types within the kidney, its expression in renal proximal tubular cells is essential for the development of high blood pressure. Besides hypertension, ACE is involved in several other renal diseases such as diabetic kidney disease, or acute kidney injury even when blood pressure is normal. In addition, studies suggest that ACE might mediate at least part of its effect through mechanisms that are independent of the Ang I conversion into Ang II and involve other substrates such as N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), Ang-(1-7), and bradykinin, among others. In this review, we summarize the recent advances in understanding the contribution of intrarenal ACE to different pathological conditions and provide insight into the many roles of ACE besides the well-known synthesis of Ang II.
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http://dx.doi.org/10.1016/j.mce.2021.111257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127398PMC
June 2021

Renal Inflammation Induces Salt Sensitivity in Male db/db Mice through Dysregulation of ENaC.

J Am Soc Nephrol 2021 May 17;32(5):1131-1149. Epub 2021 Mar 17.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California

Background: Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown.

Methods: Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension.

Results: Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice.

Conclusions: The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.
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http://dx.doi.org/10.1681/ASN.2020081112DOI Listing
May 2021

Treatment of WHO Grade 2 Meningiomas With Stereotactic Radiosurgery: Identification of an Optimal Group for SRS Using RPA.

Int J Radiat Oncol Biol Phys 2021 Jul 3;110(3):804-814. Epub 2021 Feb 3.

Department of Neurologic Surgery, University of Virginia Health System, Charlottesville, Virginia.

Purpose: This study assesses a large multi-institutional database to present the outcomes of World Health Organization grade 2 meningiomas treated with stereotactic radiosurgery (SRS). We also compare the 3-year progression-free survival (PFS) to that reported in the Radiation Therapy Oncology Group 0539 phase 2 cooperative group meningioma trial.

Methods And Materials: From an international, multicenter group, data were collected for grade 2 meningioma patients treated with SRS for demonstrable tumor from 1994 to 2019. Statistical methods used included the Kaplan-Meier method, Cox proportional hazards analysis, and recursive partitioning analysis.

Results: Two hundred thirty-three patients treated at 12 institutions were included. Patients presented at a median age of 60 years (range, 13-90), and many had at least 2 prior resections (30%) or radiation therapy (22%). Forty-eight percent of patients had prior gross total resection. At SRS, the median treatment volume was 6.1 cm (0.1-97.6). A median 15 Gy (10-30) was delivered to a median percent isodose of 50 (30-80), most commonly in 1 fraction (95%). A model was developed using recursive partitioning analysis, with one point attributed to age >50 years, treatment volume >11.5 cm, and prior radiation therapy or multiple surgeries. The good-prognostic group (score, 0-1) had improved PFS (P < .005) and time to local failure (P < .005) relative to the poor-prognostic group (score, 2-3). Age >50 years (hazard ratio = 1.85 [95% confidence interval, 1.09-3.14]) and multiple prior surgeries (hazard ratio = 1.80 [1.09-2.99]) also portended reduced PFS in patients without prior radiation therapy. Two hundred eighteen of 233 patients in this study qualified for the high-risk group of Radiation Therapy Oncology Group 0539, and they demonstrated similar outcomes (3-year PFS: 53.9% vs 58.8%). The good-prognostic group of SRS patients demonstrated slightly improved outcomes (3-year PFS: 63.1% vs 58.8%).

Conclusions: SRS should be considered in carefully selected patients with atypical meningiomas. We suggest the use of our good-prognostic group to optimize patient selection, and we strongly encourage the initiation of a clinical trial to prospectively validate these outcomes.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.048DOI Listing
July 2021

Tumors exploit CXCR4CD62L aged neutrophils to facilitate metastatic spread.

Oncoimmunology 2021 01 20;10(1):1870811. Epub 2021 Jan 20.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Granulocytes are key players in cancer metastasis. While tumor-induced expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs) is well-described, the fate and contribution of terminally differentiated mature neutrophils to the metastatic process remain poorly understood. Here, we show that in experimental metastatic cancer models, CXCR4CD62L aged neutrophils accumulate via disruption of neutrophil circadian homeostasis and direct stimulation of neutrophil aging mediated by angiotensin II. Compared to CXCR4CD62L naive neutrophils, aged neutrophils more robustly promote tumor migration and support metastasis through the increased release of several metastasis-promoting factors, including neutrophil extracellular traps (NETs), reactive oxygen species, vascular endothelial growth factors, and metalloproteinases (MMP-9). Adoptive transfer of aged neutrophils significantly enhanced metastasis of breast (4T1) and melanoma (B16LS9) cancer cells to the liver, and these effects were predominantly mediated by NETs. Our results highlight that in addition to modulating MDSC production, targeting aged neutrophil clearance and homeostasis may be effective in reducing cancer metastasis.
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http://dx.doi.org/10.1080/2162402X.2020.1870811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833766PMC
January 2021

Stereotactic Radiosurgery for Atypical (World Health Organization II) and Anaplastic (World Health Organization III) Meningiomas: Results From a Multicenter, International Cohort Study.

Neurosurgery 2021 04;88(5):980-988

Department of Neurologic Surgery, Mayfield Clinic, Cincinnati, Ohio.

Background: Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described.

Objective: To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs.

Methods: An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model.

Results: A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P < .05) and a Ki-67 index > 15% (HR = 1.66, P < .03) negatively correlated with PFS. MMs (HR = 3.21, P < .05), increased age (HR = 1.04, P = .04), and reduced KPS (HR = 0.95, P = .04) were associated with shortened OS. Adjuvant versus salvage SRS did not impact PFS/OS. A shortened interval between surgery and SRS improved PFS for AMs (HR = 0.99, P = .02) on subgroup analysis. Radiation necrosis occurred in 34 (12.5%) patients. Five-year rates of repeat surgery/radiation were 33.8% and 60.4%, respectively.

Conclusion: AM/MMs remain challenging tumors to treat. Elevated proliferative indices are associated with tumor recurrence, while MMs have worse survival. SRS can control AM/MMs in the short term, but the 5-yr PFS rates are low, underscoring the need for improved treatment options for these patients.
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http://dx.doi.org/10.1093/neuros/nyaa553DOI Listing
April 2021

Vascular contributions to cognitive impairment and dementia (VCID): A report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop.

Alzheimers Dement 2020 12 8;16(12):1714-1733. Epub 2020 Oct 8.

National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.
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http://dx.doi.org/10.1002/alz.12157DOI Listing
December 2020

Activation of AT receptors prevents diabetic complications in female db/db mice by NO-mediated mechanisms.

Br J Pharmacol 2020 10 13;177(20):4766-4781. Epub 2020 Sep 13.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Background And Purpose: The AT receptor plays a role in metabolism by opposing the actions triggered by the AT receptors. Activation of AT receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT receptors activation improves metabolism in diabetic mice.

Experimental Approach: Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT agonist, compound 21 (C21, 0.3 mg·kg ·day , s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml , drinking water).

Key Results: C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME.

Conclusion And Implications: Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.
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http://dx.doi.org/10.1111/bph.15241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520448PMC
October 2020

Effect of Anatomic Segment Involvement on Stereotactic Radiosurgery for Facial Nerve Schwannomas: An International Multicenter Cohort Study.

Neurosurgery 2020 12;88(1):E91-E98

Department of Neurosurgery, University of Virginia Medical Center, Charlottesville, Virginia.

Background: Facial nerve schwannomas are rare, challenging tumors to manage due to their nerve of origin. Functional outcomes after stereotactic radiosurgery (SRS) are incompletely defined.

Objective: To analyze the effect of facial nerve segment involvement on functional outcome for these tumors.

Methods: Patients who underwent single-session SRS for facial nerve schwannomas with at least 3 mo follow-up at 11 participating centers were included. Preoperative and treatment variables were recorded. Outcome measures included radiological tumor response and neurological function.

Results: A total of 63 patients (34 females) were included in the present study. In total, 75% had preoperative facial weakness. Mean tumor volume and margin dose were 2.0 ± 2.4 cm3 and 12.2 ± 0.54 Gy, respectively. Mean radiological follow-up was 45.5 ± 38.9 mo. Progression-free survival at 2, 5, and 10 yr was 98.1%, 87.2%, and 87.2%, respectively. The cumulative proportion of patients with regressing tumors at 2, 5, and 10 yr was 43.1%, 63.6%, and 63.6%, respectively. The number of involved facial nerve segments significantly predicted tumor progression (P = .04). Facial nerve function was stable or improved in 57 patients (90%). Patients with involvement of the labyrinthine segment of the facial nerve were significantly more likely to have an improvement in facial nerve function after SRS (P = .03). Hearing worsened in at least 6% of patients. Otherwise, adverse radiation effects included facial twitching (3 patients), facial numbness (2 patients), and dizziness (2 patients).

Conclusion: SRS for facial nerve schwannomas is effective and spares facial nerve function in most patients. Some patients may have functional improvement after treatment, particularly if the labyrinthine segment is involved.
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http://dx.doi.org/10.1093/neuros/nyaa313DOI Listing
December 2020

Role of angiotensin-converting enzyme in myeloid cell immune responses.

Cell Mol Biol Lett 2020 25;25:31. Epub 2020 May 25.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048 USA.

Angiotensin-converting enzyme (ACE), a dicarboxypeptidase, plays a major role in the regulation of blood pressure by cleaving angiotensin I into angiotensin II (Ang II), a potent vasoconstrictor. Because of its wide substrate specificity and tissue distribution, ACE affects many diverse biological processes. In inflammatory diseases, including granuloma, atherosclerosis, chronic kidney disease and bacterial infection, ACE expression gets upregulated in immune cells, especially in myeloid cells. With increasing evidences connecting ACE functions to the pathogenesis of these acquired diseases, it is suggested that ACE plays a vital role in immune functions. Recent studies with mouse models of bacterial infection and tumor suggest that ACE plays an important role in the immune responses of myeloid cells. Inhibition of ACE suppresses neutrophil immune response to bacterial infection. In contrast, ACE overexpression in myeloid cells strongly induced bacterial and tumor resistance in mice. A detailed biochemical understanding of how ACE activates myeloid cells and which ACE peptide(s) (substrate or product) mediate these effects could lead to the development of novel therapies for boosting immunity against a variety of stimuli, including bacterial infection and tumor.
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http://dx.doi.org/10.1186/s11658-020-00225-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249647PMC
February 2021

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study.

JAMA Oncol 2020 07;6(7):1028-1037

Department of Neurosurgery, New York University Langone Medical Center, New York.

Importance: Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited.

Objective: To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT.

Design, Setting, And Participants: FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019.

Interventions: SRS and WBRT for small cell lung cancer brain metastases.

Main Outcomes And Measures: Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses.

Results: In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results.

Conclusions And Relevance: Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.
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http://dx.doi.org/10.1001/jamaoncol.2020.1271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273318PMC
July 2020

Overexpression of ACE in Myeloid Cells Increases Immune Effectiveness and Leads to a New Way of Considering Inflammation in Acute and Chronic Diseases.

Curr Hypertens Rep 2020 01 8;22(1). Epub 2020 Jan 8.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

Purpose Of Review: To review recent studies exploring how myeloid cell overexpression of angiotensin-converting enzyme (ACE) affects the immune response and to formulate an approach for considering the effectiveness of inflammation in cardiovascular disease RECENT FINDINGS: While it is widely appreciated that the renin-angiotensin system affects aspects of inflammation through the action of angiotensin II, new studies reveal a previously unknown role of ACE in myeloid cell biology. This was apparent from analysis of two mouse lines genetically modified to overexpress ACE in monocytes/macrophages or neutrophils. Cells overexpressing ACE demonstrated an increased immune response. For example, mice with increased macrophage ACE expression have increased resistance to melanoma, methicillin-resistant Staphylococcus aureus, a mouse model of Alzheimer's disease, and ApoE-knockout-induced atherosclerosis. These data indicate the profound effect of increasing myeloid cell function. Further, they suggest that an appropriate way to evaluate inflammation in both acute and chronic diseases is to ask whether the inflammatory infiltrate is sufficient to eliminate the immune challenge. The expression of ACE by myeloid cells induces a heightened immune response by these cells. The overexpression of ACE is associated with immune function beyond that possible by wild type (WT) myeloid cells. A heightened immune response effectively resolves disease in a variety of acute and chronic models of disease including models of Alzheimer's disease and atherosclerosis.
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http://dx.doi.org/10.1007/s11906-019-1008-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213017PMC
January 2020

ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP.

J Biol Chem 2020 01 23;295(5):1369-1384. Epub 2019 Dec 23.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048

Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7-3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4-3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5β (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.
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http://dx.doi.org/10.1074/jbc.RA119.011244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996878PMC
January 2020

Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease.

Brain 2020 01;143(1):336-358

Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-β1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (∼3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-β1-42, vascular and parenchymal amyloid-β deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-β plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and ∼60% lower tumour necrosis factor-α (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-β1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-β1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-β conformers as well as substantially more effective amyloid-β1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and ∼80% increased extracellular degradation of amyloid-β1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-α), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer's-related amyloid-β1-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-β forms.
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http://dx.doi.org/10.1093/brain/awz364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935752PMC
January 2020

Overexpression of myeloid angiotensin-converting enzyme (ACE) reduces atherosclerosis.

Biochem Biophys Res Commun 2019 12 12;520(3):573-579. Epub 2019 Oct 12.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Background: Macrophages are ubiquitous in all stages of atherosclerosis, exerting tremendous impact on lesion progression and plaque stability. Because macrophages in atherosclerotic plaques express angiotensin-converting enzyme (ACE), current dogma posits that local myeloid-mediated effects worsen the disease. In contrast, we previously reported that myeloid ACE overexpression augments macrophage resistance to various immune challenges, including tumors, bacterial infection and Alzheimer's plaque deposition. Here, we sought to assess the impact of myeloid ACE on atherosclerosis.

Methods: A mouse model in which ACE is overexpressed in myelomonocytic lineage cells, called ACE10, was generated and sequentially crossed with ApoE-deficient mice to create ACEApoE (ACE10/ApoE). Control mice were ACEApoE (WT/ApoE). Atherosclerosis was induced using an atherogenic diet alone, or in combination with unilateral nephrectomy plus deoxycorticosterone acetate (DOCA) salt for eight weeks.

Results: With an atherogenic diet alone or in combination with DOCA, the ACE10/ApoE mice showed significantly less atherosclerotic plaques compared to their WT/ApoE counterparts (p < 0.01). When recipient ApoE mice were reconstituted with ACE bone marrow, these mice showed significantly reduced lesion areas compared to recipients reconstituted with wild type bone marrow. Furthermore, transfer of ACE-deficient bone marrow had no impact on lesion area.

Conclusion: Our data indicate that while myeloid ACE may not be required for atherosclerosis, enhanced ACE expression paradoxically reduced disease progression.
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http://dx.doi.org/10.1016/j.bbrc.2019.10.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916669PMC
December 2019

ATP release drives heightened immune responses associated with hypertension.

Sci Immunol 2019 06;4(36)

Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

The cause of most hypertensive disease is unclear, but inflammation appears critical in disease progression. However, how elevated blood pressure initiates inflammation is unknown, as are the effects of high blood pressure on innate and adaptive immune responses. We now report that hypertensive mice have increased T cell responses to antigenic challenge and develop more severe T cell-mediated immunopathology. A root cause for this is hypertension-induced erythrocyte adenosine 5'-triphosphate (ATP) release, leading to an increase in plasma ATP levels, which begins soon after the onset of hypertension and stimulates P2X7 receptors on antigen-presenting cells (APCs), increasing APC expression of CD86. Hydrolyzing ATP or blocking the P2X7 receptor eliminated hypertension-induced T cell hyperactivation. In addition, pharmacologic or genetic blockade of P2X7 receptor activity suppressed the progression of hypertension. Consistent with the results in mice, we also found that untreated human hypertensive patients have significantly elevated plasma ATP levels compared with treated hypertensive patients or normotensive controls. Thus, a hypertension-induced increase in extracellular ATP triggers augmented APC and T cell function and contributes to the immune-mediated pathologic changes associated with hypertensive disease.
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http://dx.doi.org/10.1126/sciimmunol.aau6426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699629PMC
June 2019

The Plethora of Angiotensin-Converting Enzyme-Processed Peptides in Mouse Plasma.

Anal Chem 2019 05 7;91(10):6440-6453. Epub 2019 May 7.

Department of Molecular Imaging and Therapy, Diabetes and Metabolism Research Institute , Beckman Research Institute of the City of Hope , Duarte , California 91010 , United States.

Angiotensin-converting enzyme (ACE) converts angiotensin I into the potent vasoconstrictor angiotensin II, which regulates blood pressure. However, ACE activity is also essential for other physiological functions, presumably through processing of peptides unrelated to angiotensin. The goal of this study was to identify novel natural substrates and products of ACE through a series of mass-spectrometric experiments. This included comparing the ACE-treated and untreated plasma peptidomes of ACE-knockout (KO) mice, validation with select synthetic peptides, and a quantitative in vivo study of ACE substrates in mice with distinct genetic ACE backgrounds. In total, 244 natural peptides were identified ex vivo as possible substrates or products of ACE, demonstrating high promiscuity of the enzyme. ACE prefers to cleave substrates with Phe or Leu at the C-terminal P2' position and Gly in the P6 position. Pro in P1' and Iso in P1 are typical residues in peptides that ACE does not cleave. Several of the novel ACE substrates are known to have biological activities, including a fragment of complement C3, the spasmogenic C3f, which was processed by ACE ex vivo and in vitro. Analyses with N-domain-inactive (NKO) ACE allowed clarification of domain selectivity toward substrates. The in vivo ACE-substrate concentrations in WT, transgenic ACE-KO, NKO, and CKO mice correspond well with the in vitro observations in that higher levels of the ACE substrates were observed when the processing domain was knocked out. This study highlights the vast extent of ACE promiscuity and provides a valuable platform for further investigations of ACE functionality.
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http://dx.doi.org/10.1021/acs.analchem.8b03828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693507PMC
May 2019

Overexpression of the C-domain of angiotensin-converting enzyme reduces melanoma growth by stimulating M1 macrophage polarization.

J Biol Chem 2019 03 22;294(12):4368-4380. Epub 2019 Jan 22.

From the Departments of Biomedical Sciences and

Angiotensin-converting enzyme (ACE) can hydrolyze many peptides and plays a central role in controlling blood pressure. Moreover, ACE overexpression in monocytes and macrophages increases resistance of mice to tumor growth. ACE is composed of two independent catalytic domains. Here, to investigate the specific role of each domain in tumor resistance, we overexpressed either WT ACE (Tg-ACE mice) or ACE lacking N- or C-domain catalytic activity (Tg-NKO and Tg-CKO mice) in the myeloid cells of mice. Tg-ACE and Tg-NKO mice exhibited strongly suppressed growth of B16-F10 melanoma because of increased ACE expression in macrophages, whereas Tg-CKO mice resisted melanoma no better than WT animals. The effect of ACE overexpression reverted to that of the WT enzyme with an ACE inhibitor but not with an angiotensin II type 1 (AT1) receptor antagonist. ACE C-domain overexpression in macrophages drove them toward a pronounced M1 phenotype upon tumor stimulation, with increased activation of NF-κB and signal transducer and activator of transcription 1 (STAT1) and decreased STAT3 and STAT6 activation. Tumor necrosis factor α (TNFα) is important for M1 activation, and TNFα blockade reverted Tg-NKO macrophages to a WT phenotype. Increased ACE C-domain expression increased the levels of reactive oxygen species (ROS) and of the transcription factor C/EBPβ in macrophages, important stimuli for TNFα expression, and decreased expression of several M2 markers, including interleukin-4Rα. Natural ACE C-domain-specific substrates are not well-described, and we propose that the peptide(s) responsible for the striking ACE-mediated enhancement of myeloid function are substrates/products of the ACE C-domain.
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http://dx.doi.org/10.1074/jbc.RA118.006275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433053PMC
March 2019

The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease.

J Am Soc Nephrol 2018 10 5;29(10):2546-2561. Epub 2018 Sep 5.

Departments of Biomedical Sciences and

Background: Recent evidence emphasizes the critical role of inflammation in the development of diabetic nephropathy. Angiotensin-converting enzyme (ACE) plays an active role in regulating the renal inflammatory response associated with diabetes. Studies have also shown that ACE has roles in inflammation and the immune response that are independent of angiotensin II. ACE's two catalytically independent domains, the N- and C-domains, can process a variety of substrates other than angiotensin I.

Methods: To examine the relative contributions of each ACE domain to the sodium retentive state, renal inflammation, and renal injury associated with diabetic kidney disease, we used streptozotocin to induce diabetes in wild-type mice and in genetic mouse models lacking either a functional ACE N-domain (NKO mice) or C-domain (CKO mice).

Results: In response to a saline challenge, diabetic NKO mice excreted 32% more urinary sodium compared with diabetic wild-type or CKO mice. Diabetic NKO mice also exhibited 55% less renal epithelial sodium channel cleavage (a marker of channel activity), 55% less renal IL-1, 53% less renal TNF-, and 53% less albuminuria than diabetic wild-type mice. This protective phenotype was not associated with changes in renal angiotensin II levels. Further, we present evidence that the anti-inflammatory tetrapeptide N-acetyl-seryl-asparyl-lysyl-proline (AcSDKP), an ACE N-domain-specific substrate that accumulates in the urine of NKO mice, mediates the beneficial effects observed in the NKO.

Conclusions: These data indicate that increasing AcSDKP by blocking the ACE N-domain facilitates sodium excretion and ameliorates diabetic kidney disease independent of intrarenal angiotensin II regulation.
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http://dx.doi.org/10.1681/ASN.2018030323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171283PMC
October 2018

Angiotensin-converting enzyme inhibitor works as a scar formation inhibitor by down-regulating Smad and TGF-β-activated kinase 1 (TAK1) pathways in mice.

Br J Pharmacol 2018 11 8;175(22):4239-4252. Epub 2018 Oct 8.

Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.

Background And Purpose: Angiotensin-converting enzyme (ACE), an important part of the renin-angiotensin system, is implicated in stimulating the fibrotic processes in the heart, lung, liver and kidney, while an ACE inhibitor (ACEI) promotes physiological tissue repair in these organs. The mechanism is closely related to TGF-β1 pathways. However, the reported effects of applying ACEIs during scar formation are unclear. Hence, we explored the anti-fibrotic effects of an ACEI and the molecular mechanisms involved in a mouse scar model.

Experimental Approach: After a full-thickness skin wound operation, ACE wild-type mice were randomly assigned to receive either ramipril, losartan or hydralazine p.o. ACE knockout (KO) mice and negative control mice only received vehicle (water). Wound/scar widths during wound healing and histological examinations were recorded at the final day. The ability of ACEI to reduce fibrosis via TGF-β1 signalling was evaluated in vitro and in vivo.

Key Results: ACE KO mice and mice that received ramipril showed narrower wound/scar width, reduced fibroblast proliferation, decreased collagen and TGF-β1 expression. ACEI attenuated the phosphorylation of small mothers against decapentaplegic (Smad2/3) and TGF-β-activated kinase 1 (TAK1) both in vitro and in vivo. The expression of ACE-related peptides varied in murine models with different drug treatments.

Conclusions And Implications: ACEI showed anti-fibrotic properties in scar formation by mediating downstream peptides to suppress TGF-β1/Smad and TGF-β1/TAK1 pathways. These findings suggest that dual inhibition of Smad and TAK1 signalling by ACEI is a useful strategy for the development of new anti-fibrotic agents.
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http://dx.doi.org/10.1111/bph.14489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193878PMC
November 2018

Angiotensin-converting enzyme in innate and adaptive immunity.

Nat Rev Nephrol 2018 05 26;14(5):325-336. Epub 2018 Mar 26.

Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.

Angiotensin-converting enzyme (ACE) - a zinc-dependent dicarboxypeptidase with two catalytic domains - plays a major part in blood pressure regulation by converting angiotensin I to angiotensin II. However, ACE cleaves many peptides besides angiotensin I and thereby affects diverse physiological functions, including renal development and male reproduction. In addition, ACE has a role in both innate and adaptive responses by modulating macrophage and neutrophil function - effects that are magnified when these cells overexpress ACE. Macrophages that overexpress ACE are more effective against tumours and infections. Neutrophils that overexpress ACE have an increased production of superoxide, which increases their ability to kill bacteria. These effects are due to increased ACE activity but are independent of angiotensin II. ACE also affects the display of major histocompatibility complex (MHC) class I and MHC class II peptides, potentially by enzymatically trimming these peptides. Understanding how ACE expression and activity affect myeloid cells may hold great promise for therapeutic manipulation, including the treatment of both infection and malignancy.
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http://dx.doi.org/10.1038/nrneph.2018.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192041PMC
May 2018

Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis.

JCI Insight 2017 11 16;2(22). Epub 2017 Nov 16.

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

The neutrophil chemoattractant proline-glycine-proline (PGP) is generated from collagen by matrix metalloproteinase-8/9 (MMP-8/9) and prolyl endopeptidase (PE), and it is concomitantly degraded by extracellular leukotriene A4 hydrolase (LTA4H) to limit neutrophilia. Components of cigarette smoke can acetylate PGP, yielding a species (AcPGP) that is resistant to LTA4H-mediated degradation and can, thus, support a sustained neutrophilia. In this study, we sought to elucidate if an antiinflammatory system existed to degrade AcPGP that is analogous to the PGP-LTA4H axis. We demonstrate that AcPGP is degraded through a previously unidentified action of the enzyme angiotensin-converting enzyme (ACE). Pulmonary ACE is elevated during episodes of acute inflammation, as a consequence of enhanced vascular permeability, to ensure the efficient degradation of AcPGP. Conversely, we suggest that this pathway is aberrant in chronic obstructive pulmonary disease (COPD) enabling the accumulation of AcPGP. Consequently, we identify a potentially novel protective role for AcPGP in limiting pulmonary fibrosis and suggest the pathogenic function attributed to ACE in idiopathic pulmonary fibrosis (IPF) to be a consequence of overzealous AcPGP degradation. Thus, AcPGP seemingly has very divergent roles: it is pathogenic in its capacity to drive neutrophilic inflammation and matrix degradation in the context of COPD, but it is protective in its capacity to limit fibrosis in IPF.
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http://dx.doi.org/10.1172/jci.insight.91923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752376PMC
November 2017

Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy.

Am J Physiol Renal Physiol 2018 04 29;314(4):F531-F542. Epub 2017 Nov 29.

Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California.

Diabetic nephropathy is a major cause of end-stage renal disease in developed countries. While angiotensin-converting enzyme (ACE) inhibitors are used to treat diabetic nephropathy, how intrarenal ACE contributes to diabetic renal injury is uncertain. Here, two mouse models with different patterns of renal ACE expression were studied to determine the specific contribution of tubular vs. glomerular ACE to early diabetic nephropathy: it-ACE mice, which make endothelial ACE but lack ACE expression by renal tubular epithelium, and ACE 3/9 mice, which lack endothelial ACE and only express renal ACE in tubular epithelial cells. The absence of endothelial ACE normalized the glomerular filtration rate and endothelial injury in diabetic ACE 3/9 mice. However, these mice developed tubular injury and albuminuria and displayed low renal levels of megalin that were similar to those observed in diabetic wild-type mice. In diabetic it-ACE mice, despite hyperfiltration, the absence of renal tubular ACE greatly reduced tubulointerstitial injury and albuminuria and increased renal megalin expression compared with diabetic wild-type and diabetic ACE 3/9 mice. These findings demonstrate that endothelial ACE is a central regulator of the glomerular filtration rate while tubular ACE is a key player in the development of tubular injury and albuminuria. These data suggest that tubular injury, rather than hyperfiltration, is the main cause of microalbuminuria in early diabetic nephropathy.
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http://dx.doi.org/10.1152/ajprenal.00523.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966765PMC
April 2018

Brain Transforming Growth Factor-β Resists Hypertension Via Regulating Microglial Activation.

Stroke 2017 09 11;48(9):2557-2564. Epub 2017 Jul 11.

From the School of Life Science and Technology, Tongji University, Shanghai, China (Y.L., T.V.Z., J.F.); The Second Affiliated Hospital of Zhejiang University (P.S.), Institute of Translational Medicine (P.S.), and Department of Physiology (X.Z.S.), Zhejiang University School of Medicine, Hangzhou, China; Department of Neurology (Y.L., L.L., P.L., P.S.) and Department of Biomedical Science (T.V.Z., K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA; and Pharmacological and Brain Sciences, University of Iowa (A.K.J.).

Background And Purpose: Hypertension is the major risk factor for stroke. Recent work unveiled that hypertension is associated with chronic neuroinflammation; microglia are the major players in neuroinflammation, and the activated microglia elevate sympathetic nerve activity and blood pressure. This study is to understand how brain homeostasis is kept from hypertensive disturbance and microglial activation at the onset of hypertension.

Methods: Hypertension was induced by subcutaneous delivery of angiotensin II, and blood pressure was monitored in conscious animals. Microglial activity was analyzed by flow cytometry and immunohistochemistry. Antibody, pharmacological chemical, and recombinant cytokine were administered to the brain through intracerebroventricular infusion. Microglial depletion was performed by intracerebroventricular delivering diphtheria toxin to CD11b-diphtheria toxin receptor mice. Gene expression profile in sympathetic controlling nucleus was analyzed by customized qRT-PCR array.

Results: Transforming growth factor-β (TGF-β) is constitutively expressed in the brains of normotensive mice. Removal of TGF-β or blocking its signaling before hypertension induction accelerated hypertension progression, whereas supplementation of TGF-β1 substantially suppressed neuroinflammation, kidney norepinephrine level, and blood pressure. By means of microglial depletion and adoptive transfer, we showed that the effects of TGF-β on hypertension are mediated through microglia. In contrast to the activated microglia in established hypertension, the resting microglia are immunosuppressive and important in maintaining neural homeostasis at the onset of hypertension. Further, we profiled the signature molecules of neuroinflammation and neuroplasticity associated with hypertension and TGF-β by qRT-PCR array.

Conclusions: Our results identify that TGF-β-modulated microglia are critical to keeping brain homeostasis responding to hypertensive disturbance.
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http://dx.doi.org/10.1161/STROKEAHA.117.017370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575981PMC
September 2017

Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils.

Blood 2017 07 17;130(3):328-339. Epub 2017 May 17.

Department of Biomedical Sciences and.

Angiotensin-converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if an ACE is important for the antibacterial effectiveness of neutrophils. ACE knockout mice or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin-resistant (MRSA). In contrast, mice overexpressing ACE in neutrophils (Neu mice) have increased resistance to MRSA and better in vitro killing of MRSA, , and ACE overexpression increased neutrophil production of reactive oxygen species (ROS) following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. Specifically, as compared with wild-type (WT) mice, there was a marked increase of superoxide generation (>twofold, < .0005) in Neu neutrophils following infection, whereas ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases reduced NAD phosphate oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of Neu mice because the enhanced resistance is lost with DPI (an inhibitor of ROS production by flavoenzymes) inhibition. Neu granulocytes also have increased neutrophil extracellular trap formation and interleukin-1β release in response to MRSA. In a mouse model of chemotherapy-induced neutrophil depletion, transfusion of ACE-overexpressing neutrophils was superior to WT neutrophils in treating MRSA infection. These data indicate a previously unknown function of ACE in neutrophil antibacterial defenses and suggest caution in the treatment of certain individuals with ACE inhibitors. ACE overexpression in neutrophils may be useful in boosting the immune response to antibiotic-resistant bacterial infection.
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http://dx.doi.org/10.1182/blood-2016-11-752006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520468PMC
July 2017

Angiotensin-converting enzyme affects the presentation of MHC class II antigens.

Lab Invest 2017 07 10;97(7):764-771. Epub 2017 Apr 10.

Department of Physiology, School of Medicine, Zhejiang University, Hangzhou, China.

Antigen processing and presentation through the MHC class II pathway is critical for activating T helper cells. Angiotensin-converting enzyme (ACE) is a carboxyl peptidase expressed by antigen-presenting cells. By analysis of ACE null (knockout), wild-type, and ACE-overexpressing (ACE10) mice and the antigen-presenting cells derived from these mice, we found that ACE has a physiological role in the processing of peptides for MHC class II presentation. The efficiency of presenting MHC class II epitopes from ovalbumin (OVA) and hen egg lysosome is markedly affected by cellular ACE levels. Mice overexpressing ACE in myeloid cells have a much more vigorous CD4 T-cell and antibody response when immunized with OVA. ACE is present in the endosomal pathway where MHC class II peptide processing and loading occur. The efficiency of MHC class II antigen presentation can be altered by ACE overexpression or ACE pharmacological inhibition. Thus, ACE is a dynamic participant in processing MHC class II peptides. Manipulation of ACE expression by antigen-presenting cells may prove to be a novel strategy to alter the immune response.
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http://dx.doi.org/10.1038/labinvest.2017.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493495PMC
July 2017

Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity.

Kidney Int 2017 04 15;91(4):856-867. Epub 2016 Dec 15.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA; CVMET Research Unit, Pfizer, Inc., Cambridge, Massachusetts, USA. Electronic address:

Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, is central to the development of salt sensitivity in this setting. Two mouse models were used: it-ACE mice in which ACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L-NAME salt challenge. While both wild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, is essential for renal angiotensin II accumulation and salt-sensitive hypertension.
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http://dx.doi.org/10.1016/j.kint.2016.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657384PMC
April 2017