Publications by authors named "Tamaki Sasaki"

68 Publications

Effect of zinc deficiency on chronic kidney disease progression and effect modification by hypoalbuminemia.

PLoS One 2021 11;16(5):e0251554. Epub 2021 May 11.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Serum zinc (Zn) levels tend to be low in chronic kidney disease (CKD) patients. This cohort study was conducted to investigate the relationship between zinc deficiency and CKD progression. Patients were classified into two groups based on Zn levels < 60 μg/dl (low-Zn group, n = 160) and ≥ 60 μg/dl (high-Zn group, n = 152). The primary outcome was defined as end-stage kidney disease (ESKD) or death and was examined over a 1-year observation period. Overall, the mean Zn level was 59.6 μg/dl and the median eGFR was 20.3 ml/min/1.73 m2. The incidence of the primary outcome was higher in the low-Zn group (p<0.001). Various Cox proportional hazards models adjusted for baseline characteristics showed higher risks of the primary outcome in the low-Zn group than in the high-Zn group. Competing risks analysis showed that low Zn levels were associated with ESKD but not with death. Moreover, in propensity score-matched analysis, the low-Zn group showed a higher risk of the primary outcome [adjusted hazard ratio 1.81 (95% confidence interval 1.02, 3.24)]. Furthermore, an interaction was observed between Zn and serum albumin levels (interaction p = 0.026). The results of this study indicate that zinc deficiency is a risk factor for CKD progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251554PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112700PMC
May 2021

Roxadustat and thyroid-stimulating hormone suppression.

Clin Kidney J 2021 May 20;14(5):1472-1474. Epub 2021 Jan 20.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Hypoxia-inducible factor prolyl-hydroxylase inhibitors belong to a new class of orally administered drugs for treating anemia in patients with chronic kidney disease (CKD). The prevalence of hypothyroidism is disproportionately high in patients with CKD on hemodialysis. We report a rapid suppression of thyroid-stimulating hormone (TSH) and decrease in free triiodothyronine (T3) and free tetraiodothyronine levels after switching from darbepoetin alfa to roxadustat in a hemodialysis patient with hypothyroidism on levothyroxine therapy. This was reversed after stopping roxadustat. Roxadustat has structural similarity with T3 and is a selective activating ligand for thyroid hormone receptor-β possibly suppressing TSH release.
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http://dx.doi.org/10.1093/ckj/sfab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087136PMC
May 2021

Renal cell carcinoma sharply captured by imaging technology at an early stage in a hemodialysis patient: Usefulness of noninvasive monochrome superb microvascular imaging.

Hemodial Int 2021 Mar 29. Epub 2021 Mar 29.

Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan.

It has been drawing much attention that type 2 diabetes mellitus is closely associated with increased incidence of numerous cancers and their poor prognosis. Consequently, malignancy has been recently recognized as one of diabetic complications in addition to various conventional complications. Furthermore, it is well known that the prevalence of renal cell carcinoma (RCC) is drastically increased in hemodialysis (HD) patients. Therefore, screening of RCCs in HD patients is a very important and urgent issue as there are no highly sensitive tumor markers for RCCs. Monochrome superb microvascular imaging (mSMI) is a relatively new Doppler ultrasound technique and is useful especially when evaluating very slow blood flow state, because this allows for imaging microvessels with low velocity in the absence of a contrast agent. Thus, mSMI might be also useful when contrast enhancement is not obvious on CT and/or contrast-enhanced ultrasonography using perflubutane or contrast agents are contraindicated. Moreover, it has been reported that mSMI could effectively detect vascularity of renal malignant tumor than benign renal mass in nondialysis patients. We propose that mSMI of ultrasonography could become one of the very useful methods for detecting RCCs at an early stage with high sensitivity in HD patients.
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http://dx.doi.org/10.1111/hdi.12928DOI Listing
March 2021

A rare case of amyloid light-chain amyloidosis with bilateral perirenal hematoma shortly after initiation of peritoneal dialysis.

CEN Case Rep 2021 Jan 7. Epub 2021 Jan 7.

Department of Nephrology and Hypertension, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.

Peritoneal dialysis (PD) is valuable for patients starting on renal replacement therapy because it preserves residual renal function, maintains hemodynamic stability, and affords higher quality of life than hemodialysis. Amyloid-related kidney disease is a rare condition and a cause of end-stage renal disease, the incidence of which appears to be rising in recent years. Hemoperitoneum is a common complication of PD. In some cases, it requires urgent treatment and careful monitoring for deterioration and potential complications. Although the kidney is a retroperitoneal organ, renal hemorrhage can cause bloody peritoneal dialysate. We encountered a rare case of amyloid light-chain amyloidosis where bilateral perirenal hematoma occurred shortly after initiation of PD. Amyloid angiopathy with increased blood vessel fragility and impaired vasoconstriction may promote bleeding. Therefore, hemoperitoneum in a patient on PD with disease causing fragile blood vessels, such as amyloidosis, should alert the physician to the possibility of underlying angiopathy.
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http://dx.doi.org/10.1007/s13730-020-00563-wDOI Listing
January 2021

Non-purine selective xanthine oxidase inhibitor ameliorates glomerular endothelial injury in Ins diabetic mice.

Am J Physiol Renal Physiol 2020 11 21;319(5):F765-F772. Epub 2020 Sep 21.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Endothelial dysfunction represents a predominant early feature of diabetes, rendering patients with diabetes prone to renal complications, e.g., proteinuria. Recent studies have indicated a possible role for xanthine oxidase (XO) in the pathogenesis of vascular dysfunctions associated with diabetes. In the present study, we investigated the contribution of XO activation on the progression of diabetic nephropathy in a mouse model using selective XO inhibitors. Male Ins2 heterozygous mice were used with wild-type mice as controls. Akita mice were treated with topiroxostat (Topi) or vehicle for 4 wk. Serum uric acid levels were significantly reduced in Akita + Topi mice compared with Akita + vehicle mice. The Akita + Topi group had a significant reduction in urinary albumin excretion compared with the Akita + vehicle group. Mesangial expansion, glomerular collagen type IV deposition, and glomerular endothelial injury (assessed by lectin staining and transmission electron microscopy) were considerably reduced in the Akita + topi group compared with the Akita + vehicle group. Furthermore, glomerular permeability was significantly higher in the Akita + vehicle group compared with the wild-type group. These changes were reduced with the administration of Topi. We conclude that XO inhibitors preserve glomerular endothelial functions and rescue compromised glomerular permeability, suggesting that XO activation plays a vital role in the pathogenesis of diabetic nephropathy.
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http://dx.doi.org/10.1152/ajprenal.00236.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789983PMC
November 2020

Impact of heavy rains of 2018 in western Japan: disaster-induced health outcomes among the population of Innoshima Island.

Heliyon 2020 May 25;6(5):e03942. Epub 2020 May 25.

Department of Public Health, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

Southwestern Japan suffered its worst rains in 2018 causing floods and mudslides, claiming 225 lives and forcing millions for evacuations. Referred as "Heisei san-jū-nenshichi-gatsugōu", the disaster was the result of incessant precipitation caused by the interaction of typhoon "Prapiroon" with the seasonal rain front "Baiu". The present epidemiological study aims to investigate disaster-induced health issues in 728 residents of Innoshima island in the Hiroshima Prefecture by comparing their clinical data in pre-disaster (2017) and disaster-hit (2018) years which was obtained from annual health screening. Comparison of data showed a significant increase in the urine protein concentration in victims following the disaster. Probing further into the household conditions, showed that a total of 59,844 households were affected with water outage during the heavy rains, which was accompanied by severe damage of sewerage pipelines with complete recovery process taking two weeks. This two weeks of the crisis forced victims to refrain from using restrooms which in turn led to infrequent urination, thereby explaining the increased urine protein concentration in victims following the disaster. The present study addresses the acute health implications caused by the water crisis and serves as a precautionary measure for disaster management council to provide enhanced aftercare services in victims in further events of natural disasters.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256463PMC
May 2020

Klotho is a novel therapeutic target in peritoneal fibrosis via Wnt signaling inhibition.

Nephrol Dial Transplant 2020 05;35(5):773-781

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Background: Long-term exposure to bioincompatible peritoneal dialysate causes the loss of mesothelial cells and accumulation of matrix proteins, leading to an increase in the thickness of the submesothelial layer, thereby limiting the long-term effectiveness of peritoneal dialysis (PD). However, the detailed molecular mechanisms underlying the process of peritoneal fibrosis have not been clearly elucidated. Wnt/β-catenin signaling pathway activation has been suggested to play a pivotal role in the development of organ fibrosis. Moreover, Klotho protein can regulate Wnt/β-catenin signaling. We examined the role of Klotho protein in reducing peritoneal fibrosis by inhibiting Wnt/β-catenin signaling.

Methods: The β-catenin-activated transgenic (BAT) driving expression of nuclear β-galactosidase reporter transgenic (BAT-LacZ) mice, the alpha-Klotho gene under control of human elongation factor 1 alpha promoter [Klotho transgenic (KLTG) and C57BL/6 background] and C57BL/6 mice [wild-type (WT)] were used. The mice received daily intraperitoneal (i.p.) injections of 4.25% glucose with lactate (PD solution) or saline as a control for 4 weeks. Other mice received daily i.p. injections of the same volume of saline (normal control).

Results: After exposure to PD, Wnt signal activation was observed on the peritoneal mesothelial cells in WT-PD mice. The peritoneal fibrosis was also accelerated in WT-PD mice. The protein expression of β-catenin and Wnt-inducible genes were also remarkably increased in WT-PD mice. On the other hand, KLTG-PD mice attenuated activation of Wnt/β-catenin signaling after exposure to PD and ameliorated the progression of peritoneal fibrosis.

Conclusions: Overexpression of Klotho protein protects the peritoneal membrane through attenuation of the Wnt/β-catenin signaling pathway. The availability of recombinant Klotho protein would provide a novel potential therapeutic target in peritoneal fibrosis.
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http://dx.doi.org/10.1093/ndt/gfz298DOI Listing
May 2020

Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.

FASEB J 2019 11 30;33(11):12253-12263. Epub 2019 Aug 30.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Multiple clinical studies have shown that bardoxolone methyl, a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with chronic kidney disease. However, whether an Nrf2 activator can protect tubules from proteinuria-induced tubular damage anti-inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of Cancer Research-derived glomerulonephritis (ICGN) mouse model of nephrosis, we examined the effects of dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice. The tubular epithelial cells of ICGN mice showed a decrease in the size and number of mitochondria, as well as the breakdown of the crista structure, whereas the number and ultrastructure of mitochondria were maintained by the dh404 treatment. To further determine the effect of dh404 on mitochondrial function, we used human proximal tubular cells . Stimulation with albumin and free fatty acid increased mitochondrial reactive oxygen species (ROS). However, dh404 administration diminished mitochondrial ROS. Our data show that dh404 significantly reduced proteinuria-induced tubular cell mitochondrial damage, suggesting that improved redox balance and mitochondrial function and suppression of inflammation underlie the cytoprotective mechanism of Nrf2 activators, including bardoxolone methyl, in diabetic kidney disease.-Nagasu, H., Sogawa, Y., Kidokoro, K., Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., Kashihara, N. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.
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http://dx.doi.org/10.1096/fj.201900217RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902727PMC
November 2019

Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using In Vivo Imaging.

Circulation 2019 07 18;140(4):303-315. Epub 2019 Feb 18.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan (K.K., H.N., M.S., E.K., T.S., N.K.).

Background: Sodium glucose cotransporter 2 inhibitors may reduce kidney hyperfiltration, thereby preventing diabetic kidney disease progression, which may in turn reduce cardiovascular risk, including heart failure. However, the mechanisms that regulate renal function responses to sodium glucose cotransporter 2 inhibition are not yet fully understood. We explored the renal protective effects of sodium glucose cotransporter 2 inhibition with empagliflozin, with a focus on glomerular hemodynamic effects and tubuloglomerular feedback using in vivo multiphoton microscopy imaging techniques.

Methods: C57BL/6 mice and spontaneously diabetic Ins2 mice were studied. The mice were treated with empagliflozin (20 mg·kg·d) and insulin for 4 weeks, and the single-nephron glomerular filtration rate was measured using multiphoton microscope. A neuronal nitric oxide synthase inhibitor (7-nitroindazole, 20 mg·kg·d) or a cyclooxygenase-2 inhibitor (SC58236, 6 mg/L), or an A1 adenosine receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1 mg·kg·d) was administered to elucidate the mechanisms of tubuloglomerular feedback signaling and single-nephron glomerular filtration rate regulation.

Results: The urinary excretion of adenosine, nitric oxide metabolites, and the prostanoid prostaglandin E2 was also quantified. The single-nephron glomerular filtration rate in the Ins2 group was higher than in controls (C57BL/6; 4.9±1.3 nL/min versus Ins2; 15.8±6.8 nL/min) and lower in Ins2 /empagliflozin to 8.0±3.3 nL/min (P<0.01). In vivo imaging also revealed concomitant afferent arteriolar dilation (P<0.01) and increased glomerular permeability of albumin in the Ins2 group. Empagliflozin ameliorated these changes (P<0.01). Urinary adenosine excretion in the Ins2/empagliflozin group was higher than in Ins2 (Ins2; 3.4±1.4 nmol/d, Ins2/empagliflozin; 11.2±3.0 nmol/d, P<0.05), whereas nitric oxide metabolites and prostaglandin E2 did not differ. A1 adenosine receptor antagonism, but not neuronal nitric oxide synthase or cyclooxygenase-2 inhibition, blocked the effect of empagliflozin on renal function. Empagliflozin increased urinary adenosine excretion and reduced hyperfiltration via afferent arteriolar constriction, effects that were abolished by A1 adenosine receptor blockade.

Conclusions: Adenosine/A1 adenosine receptor pathways play a pivotal role in the regulation of the single-nephron glomerular filtration rate via tubuloglomerular feedback mechanisms in response to sodium glucose cotransporter 2 inhibition, which may contribute to renal and cardiovascular protective effects reported in clinical trials.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037418DOI Listing
July 2019

The eNOS-NO pathway attenuates kidney dysfunction via suppression of inflammasome activation in aldosterone-induced renal injury model mice.

PLoS One 2018 3;13(10):e0203823. Epub 2018 Oct 3.

Department of Nephrology and Hypertension Kawasaki Medical School, Kurashiki, Okayama, Japan.

Hypertension causes vascular complications, such as stroke, cardiovascular disease, and chronic kidney disease (CKD). The relationship between endothelial dysfunction and progression of kidney disease is well known. However, the relationship between the eNOS-NO pathway and chronic inflammation, which is a common pathway for the progression of kidney disease, remains unexplored. We performed in vivo experiments to determine the role of the eNOS-NO pathway by using eNOS-deficient mice in a hypertensive kidney disease model. All mice were unilateral nephrectomized (Nx). One week after Nx, the mice were randomly divided into two groups: the aldosterone infusion groups and the vehicle groups. All mice also received a 1% NaCl solution instead of drinking water. The aldosterone infusion groups were treated with hydralazine to correct blood pressure differences. After four weeks of drug administration, all mice were euthanized, and blood and kidney tissue samples were collected. In the results, NLRP3 inflammasome activation was elevated in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. We revealed that endothelial function, particularly the eNOS-NO pathway, attenuates the progression of renal tubulointerstitial injury via suppression of inflammasome activation. Clinically, patients who develop vascular endothelial dysfunction have lifestyle diseases, such as hypertension or diabetes, and are known to be at risk for CKD. Our study suggests that the eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203823PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169882PMC
April 2019

5-Aminolevulinic acid exerts renoprotective effect via Nrf2 activation in murine rhabdomyolysis-induced acute kidney injury.

Nephrology (Carlton) 2019 Jan;24(1):28-38

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan.

Aim: Acute kidney injury (AKI) is associated with chronic kidney disease, as well as high mortality, but effective treatments for AKI are still lacking. A recent study reported the prevention of renal injury, such as ischemia-reperfusion injury, by 5-aminolevulinic acid (ALA), which induces an antioxidant effect. The current study aimed to investigate the effect of ALA in a rhabdomyolysis-induced mouse model of AKI created by intramuscular injection of 50% glycerol.

Methods: Rhabdomyolysis-induced AKI was induced by an intramuscular injection of glycerol (5 mL/kg body weight) into mice. Administration of ALA (30 mg/kg, by gavage) was started from 48 h before or 24 h after glycerol injection. The mice were sacrificed at 72 h after glycerol injection. The roles of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), which is one of the Nrf2-related antioxidants, were further investigated through in vivo and in vitro methods.

Results: 5-aminolevulinic acid markedly reduced renal dysfunction and tubular damage in mice with rhabdomyolysis-induced AKI. ALA administration decreased oxidative stress, macrophage infiltration, and inflammatory cytokines and apoptosis. The expression of Nrf2 was upregulated by ALA administration. However, administration of Zinc protoporphyrin-9 (ZnPPIX) to inhibit HO-1 activity did not abolish these improvements by ALA. The expression of Nrf2-associated antioxidant factors other than HO-1 was also increased.

Conclusion: These findings indicate that ALA exerts its antioxidant activity via Nrf2-associated antioxidant factors to provide a renoprotective effect against rhabdomyolysis-induced AKI.
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http://dx.doi.org/10.1111/nep.13189DOI Listing
January 2019

Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice.

Sci Rep 2017 08 18;7(1):8801. Epub 2017 Aug 18.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1β in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow-derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD.
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http://dx.doi.org/10.1038/s41598-017-08054-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562821PMC
August 2017

Colchicine attenuates renal fibrosis in a murine unilateral ureteral obstruction model.

Mol Med Rep 2017 Jun 2;15(6):4169-4175. Epub 2017 May 2.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama 701‑0192, Japan.

The present study aimed to assess the effects of colchicine, a known anti‑inflammatory agent, on renal fibrosis using a murine model of unilateral ureteral obstruction (UUO). Male C57BL/6 mice were divided into two groups, vehicle‑ and colchicine‑treated. Colchicine (0.5 mg/kg/day) was administered by osmotic pump, and the UUO procedure was performed on the left kidney 7 days later. The mice were sacrificed at 14 days following UUO. Colchicine treatment suppressed interstitial fibrosis of the UUO kidneys. In addition, fibrogenic gene expression in the UUO kidneys was decreased by colchicine administration. NRK‑49F normal rat kidney fibroblasts were cultured with or without colchicine under angiotensin II stimulation, following which a wound‑healing assay and actin fiber staining were performed to evaluate the effects of colchicine in vitro. Colchicine was demonstrated to inhibit angiotensin II‑induced fibroblast migration in vitro in a concentration‑dependent manner. Colchicine treatment also suppressed the angiotensin II‑induced activation of Ras homolog gene family member A in NRK‑49F cells. In conclusion, colchicine treatment significantly inhibited fibroblast activity in vitro and attenuated renal fibrosis in vivo in UUO‑operated mice. Therefore, the prevention of renal fibrosis following injury may represent a novel therapeutic application for colchicine.
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http://dx.doi.org/10.3892/mmr.2017.6539DOI Listing
June 2017

Clearance Gap: Does It Really Matter for the Evaluation of Vascular Access Function?

Contrib Nephrol 2017 12;189:246-251. Epub 2016 Dec 12.

Backgrounds: Vascular access (VA) stenosis increases the risk of VA obstruction due to the gradual progress of intimal thickening. Therefore, we should try to detect VA stenosis early. However, we do not have a cutoff for when a difference between prescribed Kt/V and delivered Kt/V reflects a clinical issue. Thus, we have devised a new index, the 'clearance gap' (CL-Gap), which quantifies the difference between the effective clearance (eCL) of a hemodialysis (HD) patient and the theoretical clearance (tCL) of a dialyzer to detect a decrease in dialysis efficiency due to VA dysfunction.

Summary: We propose a qualitative technique of analyzing dialysis (the CL-Gap method) concerning Kt/V by estimating the eCL based on the delivered Kt/V and the difference with the tCL based on the dialyzer. When VA recirculation and blood removal failure occurs, the eCL decreases, and it is expected that the CL-Gap increases. On the contrary, if uniform internal removal occurs, the eCL rises when we overestimate the delivered Kt/V and the CL-Gap is expected to decrease. However, we cannot judge whether a high CL-Gap indicates VA dysfunction immediately because it is necessary to consider not only VA dysfunction, but also the effect of other factors on the CL-Gap. Key Messages: We believe that it is important to think about VA function in a qualitative manner when managing the dose using the CL-Gap to achieve better dialysis treatment.
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http://dx.doi.org/10.1159/000450814DOI Listing
January 2018

Feasibility of fluorescence energy transfer system for imaging the renoprotective effects of aliskiren in diabetic mice.

J Renin Angiotensin Aldosterone Syst 2016 Apr-Jun;17(2):1470320315625704. Epub 2016 May 23.

Department of Nephrology and Hypertension, Kawasaki Medical School, Japan.

Introduction: We investigated the feasibility of using a fluorescence resonance energy transfer system to image enzymatic activity in order to evaluate the effects of aliskiren (a direct renin inhibitor) on diabetic nephropathy.

Materials And Methods: First, we induced diabetes in C57BL/6J mice using streptozotocin, then treated them with either aliskiren (25 mg/kg/day) or the angiotensin type 1 receptor blocker valsartan (15 mg/kg/day) for four weeks. Finally, we utilized renin fluorescence resonance energy transfer substrate to assess renin activity.

Results: Renin activity was much higher in the kidneys of diabetic mice compared to those of the non-diabetic control mice. While aliskiren inhibited this activity, valsartan did not. We noted that production of reactive oxygen species intensified and the bioavailability of nitric oxide diminished in the glomeruli of diabetic mice. Aliskiren and valsartan significantly ameliorated these effects. They suppressed glomerular production of reactive oxygen species and urinary albumin excretion. In fact, urinary albumin excretion in diabetic mice treated with aliskiren or valsartan was lower than that in untreated diabetic mice. Furthermore, aliskiren and valsartan significantly reduced glomerular permeability by maintaining the glomerular endothelial surface layer.

Conclusion: Fluorescence resonance energy transfer could provide a new tool for evaluating tissue and plasma enzymatic activity.
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http://dx.doi.org/10.1177/1470320315625704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841571PMC
January 2017

Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice.

Clin Exp Nephrol 2016 Oct 19;20(5):671-678. Epub 2015 Nov 19.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.

Background: Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy.

Methods: Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured.

Results: We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines.

Conclusion: Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways.
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http://dx.doi.org/10.1007/s10157-015-1202-3DOI Listing
October 2016

Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice.

Lab Invest 2016 Jan 9;96(1):25-36. Epub 2015 Nov 9.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Increased generation of reactive oxygen species (ROS) is a common denominative pathogenic mechanism underlying vascular and renal complications in diabetes mellitus. Endothelial NAD(P)H oxidase is a major source of vascular ROS, and it has an important role in endothelial dysfunction. We hypothesized that activation of endothelial NAD(P)H oxidase initiates and worsens the progression of diabetic nephropathy, particularly in the development of albuminuria. We used transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NAD(P)H oxidase, Nox2 (NOX2TG). NOX2TG mice were crossed with Akita insulin-dependent diabetic (Akita) mice that develop progressive hyperglycemia. We compared the progression of diabetic nephropathy in Akita versus NOX2TG-Akita mice. NOX2TG-Akita mice and Akita mice developed significant albuminuria above the baseline at 6 and 10 weeks of age, respectively. Compared with Akita mice, NOX2TG-Akita mice exhibited higher levels of NAD(P)H oxidase activity in glomeruli, developed glomerular endothelial perturbations, and attenuated expression of glomerular glycocalyx. Moreover, in contrast to Akita mice, the NOX2TG-Akita mice had numerous endothelial microparticles (blebs), as detected by scanning electron microscopy, and increased glomerular permeability. Furthermore, NOX2TG-Akita mice exhibited distinct phenotypic changes in glomerular mesangial cells expressing α-smooth muscle actin, and in podocytes expressing increased levels of desmin, whereas the glomeruli generated increased levels of ROS. In conclusion, activation of endothelial NAD(P)H oxidase in the presence of hyperglycemia initiated and exacerbated diabetic nephropathy characterized by the development of albuminuria. Moreover, ROS generated in the endothelium compounded glomerular dysfunctions by altering the phenotypes of mesangial cells and compromising the integrity of the podocytes.
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http://dx.doi.org/10.1038/labinvest.2015.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874489PMC
January 2016

Excess aldosterone is a critical danger signal for inflammasome activation in the development of renal fibrosis in mice.

FASEB J 2015 Sep 8;29(9):3899-910. Epub 2015 Jun 8.

*Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.

High levels of aldosterone impair renal function by activating proinflammatory and profibrotic pathways. However, the molecular mechanism underlying aldosterone-induced inflammation and fibrosis is unknown. Inflammasome activation contributes to chronic kidney disease. We hypothesized that aldosterone induces renal tubulointerstitial inflammation and fibrosis by activating the inflammasome. Infusing wild-type mice with aldosterone (0.25 mg/kg/d) caused tubulointerstitial damage, increased expression of inflammasome components, caspase 1 activation, and overproduction of IL-1β and IL-18. These changes were suppressed by eplerenone treatment (100 mg/kg/d) in wild-type mice or in mice deficient in apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC). Caspase 1-positive and F4/80-positive cells colocalized in the interstitium. Bone marrow transplantation using ASC-deficient mice indicated that inflammasome activation in macrophages mediated aldosterone-induced renal fibrosis. IL-18 was detected in culture supernatants of macrophages treated with aldosterone, and mitochondria-derived reactive oxygen species activated the inflammasome in these macrophages. Our results indicate that exposure of macrophages to high levels of aldosterone resulted in the activation of inflammasomes via the mitochondria-derived reactive oxygen species. Thus, inflammasome activation in macrophages may serve as a new therapeutic target for chronic kidney disease.
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http://dx.doi.org/10.1096/fj.15-271734DOI Listing
September 2015

Prevalence of gastroesophageal reflux disease symptoms and effects of esomeprazole on the quality of life related to reflux and dyspepsia in patients on maintenance hemodialysis.

Clin Exp Nephrol 2016 Feb 31;20(1):134-42. Epub 2015 May 31.

Department of Nephrology and Hypertension, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.

Background: The prevalence of gastroesophageal reflux disease (GERD) symptoms has not been investigated in patients on maintenance hemodialysis in Japan, and few studies have reported the effect of proton pump inhibitors (PPIs) in hemodialysis patients with GERD symptoms. Here, we investigated the prevalence of GERD symptoms and the effects of the PPI esomeprazole on the quality of life related to reflux and dyspepsia in patients on maintenance hemodialysis.

Methods: This was a cross-sectional/cohort study of hemodialysis outpatients implemented in 10 Japanese medical facilities from October 2012 to March 2014. The trial was registered in the UMIN Clinical Trial Registry (UMIN000009124).

Results: Forty-one of 385 patients (11%) reported GERD symptoms on the Global Overall Symptom (GOS) questionnaire. Multivariate logistic regression analysis identified the independent prognostic factors for GERD symptoms as a history of gastric ulcer and use of sevelamer hydrochloride or calcium polystyrene sulfonate. Participants with GERD symptoms completed the Quality of Life in Reflux and Dyspepsia, Japanese version (QOLRAD-J) questionnaire and were assigned to receive 4-week esomeprazole treatment (20 mg/day). This PPI therapy significantly improved all QOLRAD-J domains in the full analysis set (n = 28) and improved the GERD symptoms listed in the GOS questionnaire. Significantly impaired disease-specific quality of life (QOL) in the QOLRAD-J domains was observed in 44.4-74.1% of patients who had symptoms before treatment. The mean GOS and QOLRAD-J scores correlated significantly.

Conclusion: Therapy with 20 mg/day esomeprazole appears to be efficacious for improving disease-specific QOL and GERD symptoms in Japanese patients on maintenance hemodialysis.
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http://dx.doi.org/10.1007/s10157-015-1130-2DOI Listing
February 2016

Relationship between vascular function indexes, renal arteriolosclerosis, and renal clinical outcomes in chronic kidney disease.

Nephrology (Carlton) 2015 Sep;20(9):585-90

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan.

Aim: Hypertension contributes critically to the development of renal arteriolosclerosis in chronic kidney disease (CKD), but the impact of vascular function indexes including central blood pressure on renal arteriolosclerosis has not been investigated. We determined whether vascular function indexes were related to renal arteriolosclerosis and renal clinical outcomes in CKD.

Methods: This cross-sectional study was implemented in our hospital. Subjects were in-patients with CKD aged ≥20 years who underwent a renal biopsy. Vascular function indexes included central systolic blood pressure (SBP), cardio-ankle vascular index (CAVI), and renal resistive index. Central SBP was measured non-invasively using an automated device. Arteriolosclerosis was assessed histologically. Renal clinical outcomes included estimated glomerular filtration rate using serum creatinine (eGFRcreat) or cystatin C (eGFRcys), and the urinary albumin-creatinine ratio.

Results: Among vascular function indexes, central SBP was weakly correlated with renal arteriolosclerosis (n = 55). Renal arteriolosclerosis was increased in hypertensive or hyperuricaemic patients, and negatively correlated with serum high-density lipoprotein (HDL) cholesterol and eGFRcys, which were independent risk factors for renal arteriolosclerosis in a stepwise multivariate regression analysis. Of the vascular function indexes, CAVI showed the strongest correlation with all renal clinical outcomes. Central SBP was correlated with only urinary albumin-creatinine ratio, while renal resistive index was correlated with eGFRcreat and urinary albumin-creatinine ratio.

Conclusion: Decreased serum HDL cholesterol was independently and most closely associated with renal arteriolosclerosis. Of the vascular function indexes, CAVI had the greatest impact on renal clinical outcomes, although it was not associated with renal arteriolosclerosis.
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http://dx.doi.org/10.1111/nep.12483DOI Listing
September 2015

Deficiency of endothelial nitric oxide signaling pathway exacerbates peritoneal fibrosis in mice.

Clin Exp Nephrol 2015 Aug 13;19(4):567-75. Epub 2014 Sep 13.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan.

Background: Long-term peritoneal dialysis (PD) causes peritoneal dysfunction and structural alterations, eventually leading to peritoneal fibrosis. The endothelial nitric oxide synthase (eNOS)-NO signaling pathway contributes to the progression of organ fibrosis. However, it remains unknown whether NO signaling is involved in the process of peritoneal fibrosis. We evaluated the role of the eNOS-NO signaling pathway in the development of peritoneal fibrosis and whether stimulation of soluble guanylate cyclase (sGC), a downstream effector of NO, could attenuate peritoneal fibrosis.

Methods: We used wild-type (WT) and eNOS-deficient mice (eNOSKO). The mice underwent mechanical peritoneal stripping-induced peritoneal fibrosis at day 0. At 3, 7, 14, and 28 days after peritoneal stripping, the mice were killed. In some eNOSKO mice, the sGC stimulator Bay 41-2272 was administered by intraperitoneal injection.

Results: In WT mice, granulomatous tissue formation was observed in the submesothelial area at days 3 and 7. After day 7, the peritoneal membrane thickness gradually decreased and peritoneal tissue was repaired with leaving only slight fibrosis at day 28. However, eNOSKO mice demonstrated more progression of peritoneal fibrosis than WT mice at 28 days after peritoneal stripping. Expression of vimentin in the thickened peritoneum was prolonged after day 7 in eNOSKO mice. Treatment with Bay 41-2272 significantly attenuated peritoneal vimentin expression and fibrosis in the eNOSKO mice.

Conclusions: Disruption of the eNOS-NO signaling pathway exacerbates peritoneal fibrosis by delaying wound healing. sGC stimulation may be a useful therapy for prevention of peritoneal fibrosis.
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http://dx.doi.org/10.1007/s10157-014-1029-3DOI Listing
August 2015

Angiotensin II regulates islet microcirculation and insulin secretion in mice.

Microcirculation 2014 Feb;21(2):112-23

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Objective: Angiotensin II causes potent increases in systemic and local pressure through its vasoconstrictive effect. Despite the importance of angiotensin II for local blood flow regulation, whether angiotensin II regulates the pancreatic islet microcirculation remains incompletely understood. We hypothesized that angiotensin II directly regulates the pancreatic islet microcirculation and thereby regulates insulin secretion. The aims of this study were to develop a new technique to visualize pancreatic islet hemodynamic changes in vivo and to analyze changes in islet circulation induced by angiotensin II or an angiotensin type 1 receptor blocker.

Methods: Using an in vivo imaging method, we observed the pancreatic islet microcirculation. Various doses of angiotensin II or an angiotensin type 1 receptor blocker were injected intravenously, and changes in islet microcirculation were observed. Glucose-stimulated insulin secretion from the pancreas was measured from the hepatic portal vein.

Results: We identified islet microcirculation using a fluorescent dye. Angiotensin II significantly induced blood vessel contraction in the islets in a dose-dependent manner. In contrast, the angiotensin type 1 receptor blocker induced vasodilation. Glucose-stimulated insulin secretion was decreased by angiotensin II infusion.

Conclusions: These results show that angiotensin II is involved in the regulation of pancreatic islet microcirculation and insulin secretion.
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http://dx.doi.org/10.1111/micc.12094DOI Listing
February 2014

Hypertension promotes islet morphological changes with vascular injury on pre-diabetic status in SHRsp rats.

Clin Exp Hypertens 2014 20;36(3):159-64. Epub 2013 Jun 20.

Department of Nephrology and Hypertension, Kawasaki Medical School , Okayama 701-0192 , Japan.

Abstract Hypertensive patients have a higher incidence of new-onset diabetic mellitus than normotensive subjects, and we hypothesized that hypertension induces morphological changes in islets via vascular injury. To test our hypothesis, we administrated hydralazine or irbesartan to spontaneously hypertensive stroke-prone (SHRsp) rats. A greater islet fibrosis was observed in SHRsp rats compared with controls, and irbesartan significantly ameliorated the fibrosis. High fat diet induced glucose intorelance in SHRsp rats and irbesartan but not hydralazine improved glucose torelance. We demonstrate islet morphological changes in hypertensive rats, and our data suggest that angiotensin receptor blockers have the potential to prevent islet injury.
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http://dx.doi.org/10.3109/10641963.2013.804539DOI Listing
December 2014

Maintenance of endothelial guanosine triphosphate cyclohydrolase I ameliorates diabetic nephropathy.

J Am Soc Nephrol 2013 Jun 25;24(7):1139-50. Epub 2013 Apr 25.

Department of Nephrology and Hypertension, Medical School, Kurashiki, Okayama, Japan.

In diabetes, endothelial nitric oxide synthase (eNOS) produces superoxide anion rather than nitric oxide, referred to as "eNOS uncoupling," which may contribute to endothelial dysfunction, albuminuria, and diabetic nephropathy. Reduced levels of endothelium-derived tetrahydrobiopterin (BH4), an essential cofactor for eNOS, promote eNOS uncoupling. Accelerated degradation of guanosine triphosphate cyclohydrolase I (GTPCH I), the rate-limiting enzyme in BH4 biosynthesis, also occurs in diabetes, suggesting that GTPCH I may have a role in diabetic microvascular disease. Here, we crossed endothelium-dominant GTPCH I transgenic mice with Ins2(+/Akita) diabetic mice and found that endothelial overexpression of GTPCH I led to higher levels of intrarenal BH4 and lower levels of urinary albumin and reactive oxygen species compared with diabetic control mice. Furthermore, GTPCH I overexpression attenuated the hyperpermeability of macromolecules observed in diabetic control mice. In addition, we treated Ins2(+/Akita) mice with metformin, which activates AMP-activated protein kinase (AMPK) and thereby slows the degradation of GTPCH I; despite blood glucose levels that were similar to untreated mice, those treated with metformin had significantly less albuminuria. Similarly, in vitro, treating human glomerular endothelial cells with AMPK activators attenuated glucose-induced reductions in phospho-AMPK, GTPCH I, and coupled eNOS. Taken together, these data suggest that maintenance of endothelial GTPCH I expression and the resulting improvement in BH4 biosynthesis ameliorate diabetic nephropathy.
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http://dx.doi.org/10.1681/ASN.2012080783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699824PMC
June 2013

Erythropoietin-producing tubercle granuloma in a hemodialysis patient.

BMC Nephrol 2013 Apr 21;14:91. Epub 2013 Apr 21.

Background: We describe a case of a fever of unknown etiology that was caused by a caseating tubercle granuloma which produced erythropoietin. To our knowledge, this is the first report of an erythropoietin- producing granuloma.

Case Presentation: A 48-year-old Japanese man with a 5-year history of maintenance hemodialysis for diabetic nephropathy presented with an intermittent fever over a few months. During febrile periods he developed erythema nodosum on his legs. Computed tomography showed axillary lymph node enlargement and this was further corroborated by a gallium scan that revealed high gallium uptake in these nodes. A Mantoux test was positive and an interferongamma release assay for tuberculosis diagnosis was also positive. Lymph node tuberculosis was suspected and the patient underwent lymphadenectomy. Histological analysis of the lymph nodes revealed a caseating granuloma that showed positive results on an acid-fast bacteria stain and a Mycobacterium tuberculosis polymerase chain reaction test. After lymphadenectomy, however, the patient's hemoglobin levels rapidly decreased from 144 to 105 g/L, and this was further compounded by a decrease in serum erythropoietin from 223 mIU/mL to 10.7 mIU/mL by postoperative day 21. We suspected the tubercle to be a source of the erythropoietin and this was further confirmed by in situ hybridization.

Conclusions: We report for the first time ectopic erythropoietin production by a tuberculous lymph node. Our observations are substantiated by a postoperative decline in his erythropoietin level and a clinical requirement for erythropoietin treatment.
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http://dx.doi.org/10.1186/1471-2369-14-91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646680PMC
April 2013

Japan Renal Biopsy Registry and Japan Kidney Disease Registry: Committee Report for 2009 and 2010.

Clin Exp Nephrol 2013 Apr 6;17(2):155-73. Epub 2013 Feb 6.

Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.
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http://dx.doi.org/10.1007/s10157-012-0746-8DOI Listing
April 2013

Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status.

Kidney Int 2013 Apr 23;83(4):662-73. Epub 2013 Jan 23.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Proteinuria is an independent risk factor for progressive renal diseases because it initiates or aggravates tubulointerstitial injury. Clinically, females are less susceptible to progression of chronic kidney disease; however, the mechanisms underlying the renoprotective effect of estrogen receptor stimulation have yet to be clarified. Recently, inflammasome-dependent inflammatory responses were shown to be triggered by free fatty acids, and mitochondria-derived reactive oxygen species were shown to be required for this response. Albumin-bound free fatty acids trigger inflammasome activation through mitochondrial reactive oxygen species production in human proximal tubule epithelial cells in vitro, an effect inhibited by raloxifene. Female ICR-derived glomerulonephritic mice (mice with hereditary nephritic syndrome) were ovariectomized and treated with raloxifene, a selective estrogen receptor modulator. Ovariectomized mice showed activation of tubular inflammasomes and elevated levels of inflammasome-dependent cytokines. Raloxifene attenuated these changes ameliorating tubulointerstitial damage, reduced production of reactive oxygen species, averted morphological changes, and improved respiratory function in mitochondria. The expression of genes that encode rate-limiting enzymes in the mitochondrial β-oxidation pathway was reduced by ovariectomy but enhanced by raloxifene. Thus, inflammasomes may be a novel and promising therapeutic target for proteinuria-induced renal injury.
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http://dx.doi.org/10.1038/ki.2012.475DOI Listing
April 2013

Angiostatin production increases in response to decreased nitric oxide in aging rat kidney.

Lab Invest 2013 Mar 7;93(3):334-43. Epub 2013 Jan 7.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan.

The development of interstitial fibrosis occurs with aging. Impaired angiogenesis, associated with progressive loss of the renal microvasculature, is thought to be a cause of age-related nephropathy. However, the mechanism of capillary loss in aging kidney has not been fully elucidated. Angiostatin is a kringle-containing fragment of plasminogen and is a potent inhibitor of angiogenesis in vivo. Whether angiostatin generation is increased in the aging kidney has not been investigated. We examined 4, 10, 16, and 24-month-old Sprague-Dawley rats for angiostatin production and found that angiostatin generation was increased in aged rats. The protein expression and the activity of cathepsin D-the enzyme for angiostatin production--were increased in aged rats. In the aging kidney, nitric oxide (NO) availability is decreased. To investigate the role of NO in angiostatin production, human umbilical vein endothelial cells were treated with L-NG-nitroarginine methyl ester (L-NAME). L-NAME-treated cells showed increased cathepsin D activity and angiostatin production. For in vivo experiments, 16- to 18-month-old rats were treated with L-NAME or molsidomine for 3 months. Angiostatin production was increased in L-NAME-treated kidney, accompanied by increased cathepsin D activity. In contrast, angiostatin production was decreased in molsidomine-treated kidney, accompanied by decreased cathepsin D activity. In conclusion, angiostatin generation by cathepsin D was increased in the aging rat kidney. Decreased NO production activated cathepsin D activity. Increased angiostatin production may be related to capillary loss and interstitial damage in the aging rat kidney.
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http://dx.doi.org/10.1038/labinvest.2012.171DOI Listing
March 2013

Establishment of a blood purification system for renal failure rats using small-size dialyzer membranes.

Ther Apher Dial 2012 Dec 7;16(6):566-72. Epub 2012 Aug 7.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Hemodialysis techniques for small animals have not been established because no small dialysis apparatus has been available. We recently developed a small-size dialyzer and established an appropriate blood purification system for small animals. To confirm the appropriate dialysate flow rate, bovine blood was dialyzed for 60 min at a fixed blood flow rate of 1.0 mL/min and variable dialysate flow rates. Blood urea nitrogen and creatinine levels decreased significantly at a dialysate flow rate of 5 mL/min (from 13.7 ± 0.2 to 10.3 ± 1.2 mg/dL and 1.07 ± 0.15 to 0.61 ± 0.12 mg/dL, respectively, P < 0.05). To determine the appropriate in vivo conditions, extracorporeal circulation was performed in anesthetized male Sprague-Dawley rats at a dialysate flow rate of 0.0 mL/min, for 240 min, and at variable blood flow rates. Extracorporeal circulation was successful at a blood flow rate of 1.0 mL/min, but not 1.5 mL/min. To establish in vivo hemodialysis conditions, we used the animal model of end stage renal failure. Sprague-Dawley rats were fed a 0.75% adenine-containing diet for 3 weeks, after which they received hemodialysis for 120 min at a dialysate and blood flow rate of 5.0 and 1.0 mL/min, respectively. There were no significant changes in systolic blood pressure or heart rate during dialysis. Thus, this blood purification system can be safely used for small animals at a dialysate flow rate of 5.0 mL/min and a blood flow rate of 1.0 mL/min. This system provides a basis for further research on hemodialysis therapy.
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http://dx.doi.org/10.1111/j.1744-9987.2012.01091.xDOI Listing
December 2012