scholarly journals Activation of Rac1-Mineralocorticoid Receptor Pathway Contributes to Renal Injury in Salt-Loaded db/db Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Daigoro Hirohama ◽  
Mitsuhiro Nishimoto ◽  
Nobuhiro Ayuzawa ◽  
Wakako Kawarazaki ◽  
Wataru Fujii ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Injury ◽  
Mineralocorticoid Receptor ◽  
Diabetic Mouse ◽  
High Salt ◽  
Glomerular Injury ◽  
Intense Staining ◽  
Guanosine Triphosphatase ◽  
Novel Strategy ◽  
End Stage

The progression of diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, involves mineralocorticoid receptor (MR) activation. We previously identified crosstalk between the small guanosine triphosphatase (GTPase) RAS-related C3 botulinus toxin substrate 1 (Rac1) and MR, but the role of Rac1-MR pathway activation in the progression of DKD is not clear. We performed uninephrectomy on type 2 diabetic mouse models, db/db (UNx-high salt [HS] db/db ), and their lean control, db/m (UNx-HS db/m ), at 4-week postpartum, and fed them a high-salt diet for 10 weeks. To evaluate the involvement of the Rac1-MR pathway in the DKD progression, we investigated the effects of the nonsteroidal MR antagonist, finerenone, and the Rac1 inhibitor, NSC23766, on blood pressure and glomerular injury in UNx-HS db/db mice. UNx-HS db/db mice with hyperaldosteronism showed hypertension and hypokalemia with increased cleaved α-epithelial sodium channel expressions and massive albuminuria, accompanied by glomerular injury with nodular lesions, which is a characteristic finding in human diabetic nephropathy. Expressions of active Rac1 and serum-and glucocorticoid-induced protein kinase 1 (Sgk1), a downstream molecule of MR signaling, in the renal cortex and isolated glomeruli, significantly elevated in UNx-HS db/db mice, associated with intense staining of active Rac1 in glomerular podocytes, but both hypertension and renal injury were ameliorated by NSC23766 and finerenone, associated with Sgk1 inhibition, suggesting that Rac1-MR activation contributes to hypertension and podocyte injury. In conclusion, salt-induced activation of Rac1-MR pathway in distal tubules and glomeruli is involved in DKD progression through hypertension and glomerular injury, respectively. This finding highlights MR antagonism along with Rac1 inhibition as a novel strategy for DKD treatment.

Alteration of the gut microbiota by vinegar is associated with amelioration of hyperoxaluria-induced kidney injury

2020 ◽  
Vol 11 (3) ◽  
pp. 2639-2653
Author(s):  
Wei Zhu ◽  
Yang Liu ◽  
Xiaolu Duan ◽  
Chenglin Xiao ◽  
Yu Lan ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Gut Microbiota ◽  
Renal Injury ◽  
Kidney Injury ◽  
End Stage Kidney Disease ◽  
End Stage

Hyperoxaluria is well known to cause renal injury and end-stage kidney disease.

scholarly journals Aging-associated renal disease in mice is fructokinase dependent

2016 ◽  
Vol 311 (4) ◽  
pp. F722-F730 ◽  
Author(s):  
Carlos A. Roncal-Jimenez ◽  
Takuji Ishimoto ◽  
Miguel A. Lanaspa ◽  
Tamara Milagres ◽  
Ana Andres Hernando ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Knockout Mice ◽  
Renal Injury ◽  
Disease Process ◽  
High Salt ◽  
Mesangial Matrix ◽  
Wild Type ◽  
High Salt Intake ◽  
Matrix Expansion

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

scholarly journals Nicorandil, a Katp channel opener, alleviates chronic renal injury by targeting podocytes and macrophages

2012 ◽  
Vol 303 (3) ◽  
pp. F339-F349 ◽  
Author(s):  
Yoshifuru Tamura ◽  
Katsuyuki Tanabe ◽  
Wataru Kitagawa ◽  
Shunya Uchida ◽  
George F. Schreiner ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Xanthine Oxidase ◽  
Renal Injury ◽  
Vascular System ◽  
K Channel ◽  
Sulfonylurea Receptor ◽  
Glomerular Injury ◽  
Tubulointerstitial Injury

Nicorandil exhibits a protective effect in the vascular system, which is thought to be due to vasodilatation from opening ATP-dependent potassium channels and donation of nitric oxide. Recently, nicorandil was shown to be renoprotective in models of acute kidney injury and glomerulonephritis. However, the specific mechanisms of renoprotection are unclear. We evaluated the effect of nicorandil on the rat remnant kidney model of chronic kidney disease. Blood pressure was unchanged by a 10-wk course of nicorandil, while albuminuria was significantly reduced. Glomerular injury and tubulointerstitial injury were also ameliorated by nicorandil. Oxidative stress, as noted by renal nitrotyrosine level and urine 8-hydroxy-2′-deoxyguanosine, were elevated in this model and was significantly reduced by nicorandil treatment. Treatment was associated with maintenance of the mitochondrial antioxidant, manganese SOD, in podocytes and with suppression of xanthine oxidase expression in infiltrating macrophages. Interestingly, these two cell types express sulfonylurea receptor 2 (SUR2), a binding site of nicorandil in the ATP-dependent K channel. Consistently, we found that stimulating SUR2 with nicorandil prevented angiotensin II-mediated upregulation of xanthine oxidase in the cultured macrophage, while xanthine oxidase expression was rather induced by blocking SUR2 with glibenclamide. In conclusion, nicorandil reduces albuminuria and ameliorates renal injury by blocking oxidative stress in chronic kidney disease.

scholarly journals P0143OPPOSING EFFECTS OF P38 MAPK IN PODOCYTES ON ALDOSTERONE-INDUCED GLOMERULAR INJURY IN POD-GC-A CKO MICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
SAYAKA SUGIOKA ◽  
Yukiko Kato ◽  
Akira Ishii ◽  
Keita Mori ◽  
Keisuke Osaki ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Renal Injury ◽  
High Salt ◽  
Glomerular Injury ◽  
Podocyte Damage ◽  
Foot Process ◽  
Genetic Deletion ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Abstract Background and Aims Previously, we demonstrated that uninephrectomized aldosterone-infused, high salt-fed podocyte-specific guanylyl cyclase-A (natriuretic peptide receptor 1) conditional KO (pod-GC-A cKO) mice exhibited glomerular injury and that pharmacological inhibition of p38 MAPK ameliorates podocyte damage. However, the effects of genetic deletion of p38 MAPK in podocytes of pod-GC-A cKO mice have been unclarified. Method We generated p38 MAPK(fl/fl);Nephrin-Cre (pod-p38 MAPK cKO) mice and p38 MAPK(fl/fl);GC-A(fl/fl);Nephrin-Cre (pod-p38MAPK/GC-A DKO) mice. For induction of glomerular injury, we treated them with aldosterone and high salt at 2 months of age for 3 weeks without nephrectomy (B-ALDO). In vitro, we examined the effect of p38 MAPK inhibitor in cultured human podocytes transfected with GC-A siRNA. Results B-ALDO-treated pod-p38 MAPK/GC-A DKO mice resulted in significant elevation of serum Cr (0.29 ± 0.04 mg/dl), massive albuminuria (42,660 ± 20,200 μg/mgCr) and severe foot process effacement in addition to intracapillary fibrin thrombi which indicated endothelial damage. Vehicle-treated DKO mice, B-ALDO-treated pod-GC-A cKO mice, and B-ALDO-treated pod-p38 MAPK cKO showed normal serum Cr levels (0.14 ± 0.01, 0.18 ± 0.02, 0.20 ± 0.01 mg/dl, respectively), mild increase of albuminuria (223 ± 6.5, 1,496 ± 592, 649 ± 303 μg/mgCr, respectively) and only segmental foot process effacement. Blood pressure was not elevated in either mutant mice compared with that of B-ALDO control mice. Furthermore, glomerular mRNA expressions of MCP-1, PAI-1, and FN were upregulated and that of VEGF-A was downregulated in DKO mice. In vitro, suppression of GC-A mRNA by siRNA in combination with p38 MAPK inhibitor downregulated VEGF mRNA in human cultured podocytes. Our previous works showed that pharmacological inhibition of p38 MAPK in the whole body ameliorated podocyte damage, whereas our current result showed that genetic deletion of p38 MAPK in podocytes aggravated renal injury. In order to explain the discrepancy in these results, we added an analysis of podocyte specific GC-A fl/fl p38 fl/+ cKO mice. Pod GC-A fl/fl p38 fl/+ cKO mice exhibited considerably milder renal damage than pod GC-A fl/fl p38 fl/fl double cKO mice. Conclusion Genetic complete p38 MAPK deletion in GC-A-nul podocytes exacerbated aldosterone-induced glomerular endothelial cell injury as well as podocytes, and resulted in renal dysfunction, probably through VEGF downregulation, whereas partial p38 MAPK inhibition in podocytes ameliorated aldosterone-induced glomerular injury in pod-GC-A cKO mice. These results suggest a certain level of p38 MAPK in podocytes is necessary to protect endothelial and epithelial cells from aldosterone-induced renal injury.

scholarly journals Sodium bicarbonate loading limits tubular cast formation independent of glomerular injury and proteinuria in Dahl salt-sensitive rats

2018 ◽  
Vol 132 (11) ◽  
pp. 1179-1197 ◽  
Author(s):  
Sarah C. Ray ◽  
Bansari Patel ◽  
Debra L. Irsik ◽  
Jingping Sun ◽  
Hiram Ocasio ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Bicarbonate ◽  
Renal Injury ◽  
High Salt ◽  
Proton Channel ◽  
Pathological Feature ◽  
Glomerular Injury ◽  
High Salt Diet ◽  
Salt Diet ◽  
Inflammatory Status

Sodium bicarbonate (NaHCO3) slows the decline in kidney function in patients with chronic kidney disease (CKD), yet the mechanisms mediating this effect remain unclear. The Dahl salt-sensitive (SS) rat develops hypertension and progressive renal injury when fed a high salt diet; however, the effect of alkali loading on kidney injury has never been investigated in this model. We hypothesized that NaHCO3 protects from the development of renal injury in Dahl salt-sensitive rats via luminal alkalization which limits the formation of tubular casts, which are a prominent pathological feature in this model. To examine this hypothesis, we determined blood pressure and renal injury responses in Dahl SS rats drinking vehicle (0.1 M NaCl) or NaHCO3 (0.1 M) solutions as well as in Dahl SS rats lacking the voltage-gated proton channel (Hv1). We found that oral NaHCO3 reduced tubular NH4+ production, tubular cast formation, and interstitial fibrosis in rats fed a high salt diet for 2 weeks. This effect was independent of changes in blood pressure, glomerular injury, or proteinuria and did not associate with changes in renal inflammatory status. We found that null mutation of Hv1 also limited cast formation in Dahl SS rats independent of proteinuria or glomerular injury. As Hv1 is localized to the luminal membrane of TAL, our data suggest that alkalization of the luminal fluid within this segment limits cast formation in this model. Reduced cast formation, secondary to luminal alkalization within TAL segments may mediate some of the protective effects of alkali loading observed in CKD patients.

scholarly journals Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Daiji Kawanami ◽  
Yuichi Takashi ◽  
Yoshimi Muta ◽  
Naoki Oda ◽  
Dai Nagata ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mineralocorticoid Receptor ◽  
Diabetic Kidney Disease ◽  
Current Knowledge ◽  
Mineralocorticoid Receptor Antagonists ◽  
Future Perspectives ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
Fibrotic Process ◽  
End Stage

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide. Mineralocorticoid receptor (MR) plays an important role in the development of DKD. A series of preclinical studies revealed that MR is overactivated under diabetic conditions, resulting in promoting inflammatory and fibrotic process in the kidney. Clinical studies demonstrated the usefulness of MR antagonists (MRAs), such as spironolactone and eplerenone, on DKD. However, concerns regarding their selectivity for MR and hyperkalemia have remained for these steroidal MRAs. Recently, nonsteroidal MRAs, including finerenone, have been developed. These agents are highly selective and have potent anti-inflammatory and anti-fibrotic properties with a low risk of hyperkalemia. We herein review the current knowledge and future perspectives of MRAs in DKD treatment.

Emerging Therapy-Related Kidney Disease

2009 ◽  
Vol 133 (2) ◽  
pp. 268-278
Author(s):  
Lois J. Arend ◽  
Tibor Nadasdy
Keyword(s):  
Kidney Disease ◽  
Renal Injury ◽  
Recent Literature ◽  
Renal Toxicity ◽  
Kidney Injury ◽  
Clinical History ◽  
Drug Induced ◽  
Stage Renal Disease ◽  
End Stage

Abstract Context.—Many new therapies have emerged within the last 5 to 10 years to treat a variety of conditions. Several of these have direct or indirect renal toxicities that may go undiagnosed without careful attention of the pathologist to a patient's clinical history, particularly the addition of new medications or treatments. Objective.—To discuss patterns of renal injury resulting from medications or therapeutic regimens that have been introduced within the last 10 years. Recognition of these patterns may allow the pathologist to alert the attending clinician to a possible drug-induced renal injury and prevent further deterioration of renal function and possible chronic kidney disease. Data Sources.—A review of recent literature and unpublished observations of case-derived material. Conclusions.—A number of newer therapies have emerged as agents of renal toxicity, producing a variety of pathologic changes in the kidney. The outcome can be acute or chronic glomerular, tubular, interstitial, and/or vascular injury. Some drugs will result in irreversible changes and end-stage renal disease, whereas many of the alterations can be reversed with removal of the offending agent, avoiding potential long-term kidney injury.

Congenital abnormalities of the kidneys and urinary tract

2019 ◽  
pp. 57-86
Author(s):  
Lesley Rees ◽  
Nicholas J.A Webb ◽  
Detlef Bockenhauer ◽  
Marilynn G. Punaro
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Kidney Disease ◽  
Tract Infection ◽  
Renal Injury ◽  
Incidental Findings ◽  
Renal Damage ◽  
Congenital Abnormalities ◽  
End Stage Kidney Disease ◽  
End Stage

Congenital abnormalities of the kidneys and urinary tract (CAKUT) are the commonest cause of renal problems in children, ranging from asymptomatic or incidental findings to a cause of urinary tract infection and obstruction, renal damage, and end-stage kidney disease. The investigation and management of CAKUT depend on the potential for causing renal injury.

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