Mineralocorticoid Receptor Blockade Enhances the Antiproteinuric Effect of an Angiotensin II Blocker through Inhibiting Podocyte Injury in Type 2 Diabetic Rats

Nishiyama, Akira; Kobori, Hiroyuki; Konishi, Yoshio; Morikawa, Takashi; Maeda, Isseki; Okumura, Michiaki; Kishida, Masatsugu; Hamada, Masahiro; Nagai, Yukiko; Nakagawa, Toshitaka; Ohashi, Naro; Nakano, Daisuke; Hitomi, Hirofumi; Imanishi, Masahito

doi:10.1124/jpet.109.158113

Cited by 43 publications

(38 citation statements)

References 43 publications

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“…14) Recent studies indicate that glomerular podocyte injury is a cardinal feature of diabetic nephropathy, and is closely involved in the progression of proteinuria, glomerular sclerosis, and tubulointerstitial injury. 14,15) In the present study, we demonstrated that nephrin and podocin protein expression were decreased and desmin staining was increased in DS rats with end-stage HF and that these expressions were restored by the V 2 R antagonist tolvaptan. Nishiyama, et al reported that podocyte injury with decreased nephrin and podocin expression is observed in some experimental models.…”

Section: Discussionmentioning

confidence: 62%

“…Nishiyama, et al reported that podocyte injury with decreased nephrin and podocin expression is observed in some experimental models. 15,16) With regard to the V 2 -mediated action of vasopressin, the use of a highly selective, orally active V 2 R antagonist, SR-121463, in diabetic rats established the critical role played by the antidiuretic effects of vasopressin in urinary albumin excretion associated with diabetes. 17) Recently, Okada, et al 18) showed that tolvaptan is protective against podocyte damage and proteinuria, and that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and function in puromycin aminonucleoside nephrosis.…”

Section: Discussionmentioning

confidence: 99%

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Renoprotective Effect of Vasopressin V2 Receptor Antagonist Tolvaptan in Dahl Rats With End-Stage Heart Failure

et al. 2013

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SummaryTolvaptan is a highly selective and orally effective arginine vasopressin V 2 receptor antagonist, and is potentially useful for the treatment of heart failure (HF) patients. However, the renoprotective effect of long-term tolvaptan therapy and its underlying mechanisms remain unknown. We evaluated the effects of chronic treatment with tolvaptan on renal dysfunction, podocyte injury, inflammation, oxidative stress, Rho-kinase, epithelial-mesenchymal transition (EMT), and the extracellular signal-regulated protein kinase (ERK1/2) pathway in the renal cortex of Dahl salt-sensitive hypertensive (DS) rats with end-stage severe HF. DS and Dahl salt-resistant rats were fed a high-salt diet at 6 weeks of age. DS rats were treated with vehicle and tolvaptan (0.05% concentration in diet) from the age of 11 to 18 weeks. Vehicle-treated DS rats developed proteinuria, renal dysfunction, glomerulosclerosis, and interstitial fibrosis, which were ameliorated by tolvaptan without changing blood pressure. Decreased expression of nephrin and podocin and increased desmin-positive area in failing rats were restored by tolvaptan. Upregulation of NAD(P)H oxidase p22 phox , p47 phox , and gp91 phox , EMT markers such as transforming growth factor-β1, vimentin, and fibronectin expression, and Rho-kinase and ERK1/2 phosphorylation in DS rats were significantly suppressed by tolvaptan. Tolvaptan administration resulted in significant inhibition of tumor necrosis factor-α and monocyte chemoattractant protein-1 expression, and nuclear factor-κB phosphorylation. We concluded that long-term tolvaptan therapy may improve renal dysfunction, glomerulosclerosis, podocyte injury, and inflammation associated with oxidative stress, as well as EMT, ERK, and the Rho-kinase pathway in the failing heart of DS rats. Thus, tolvaptan may be a therapeutic strategy for end-stage severe HF. (Int Heart J 2013; 54: 98-106)

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Renoprotective Effect of Vasopressin V2 Receptor Antagonist Tolvaptan in Dahl Rats With End-Stage Heart Failure

et al. 2013

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“…24 Furthermore, systemic MR blockade reduces podocyte loss or damage in diabetic rats. 11,12 Therefore, our data showing a lack of prevention of albuminuria in diseased mice with systemic MR blockade or podocyte MR deficiency indicates that podocyte damage in this rapidly progressive GN model is mediated by injury mechanisms that are independent of MR. However, the ability of MR antagonists to reduce proteinuria in CKD, suggests that podocyte MR signaling may play a role in chronic proteinuria.…”

Section: Discussionmentioning

confidence: 97%

“…2,3,5,11 These studies also link MR blockade to suppression of leukocyte recruitment and podocyte injury. This suggests that the major pathologic effects of MR signaling may occur in podocytes and inflammatory cells.…”

mentioning

confidence: 99%

Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

Huang

Nikolic-Paterson

Han

et al. 2014

Journal of the American Society of Nephrology

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Clinical and experimental studies have shown that mineralocorticoid receptor (MR) antagonists substantially reduce kidney injury. However, the specific cellular targets and mechanisms by which MR antagonists protect against kidney injury must be identified. PodMRKO) to establish the role of MR in these cell types in the development of mouse GN. Accelerated anti-glomerular basement membrane GN was examined in groups of mice: MyMRKO, PodMRKO, wildtype (WT) littermates, and WT mice receiving eplerenone (100 mg/kg twice a day; EPL-treated). At day 15 of disease, WT mice had glomerular crescents (37%65%), severe proteinuria, and a 6-fold increase in serum cystatin-C. MyMRKO, PodMRKO, and EPL-treated mice with GN displayed proteinuria similar to that in these disease controls. However, MyMRKO and EPL-treated groups had a 35% reduction in serum cystatin-C levels and reduced crescent numbers compared with WT mice, whereas PodMRKO mice were not protected. The protection observed in MyMRKO mice appeared to result predominantly from reduced recruitment of macrophages and neutrophils into the inflamed kidney. Suppression of kidney leukocyte accumulation in MyMRKO mice correlated with reductions in gene expression of proinflammatory molecules (TNF-a, inducible nitric oxide synthase, chemokine (C-C motif) ligand 2, matrix metalloproteinase-12), tubular damage, and renal fibrosis and was similar in EPL-treated mice. In conclusion, MR signaling in myeloid cells, but not podocytes, contributes to the progression of renal injury in mouse GN, and myeloid deficiency of MR provides protection similar to eplerenone in this disease.

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“…Moreover, treatment with tempol or eplerenone markedly attenuated podocyte injury and proteinuria in other rodent models of hypertensive glomerulosclerosis (14,48,50). We also showed that eplerenone attenuated podocyte injury and proteinuria in type 2 diabetic rats (51). Preliminary experiments have shown that aldosterone significantly protracts wound healing in cultured mouse podocytes (52), although the precise molecular mechanisms are not yet clear.…”

Section: Podocyte Injury and Aldosteronementioning

confidence: 79%

Pathophysiological Roles of Aldosterone and Mineralocorticoid Receptor in the Kidney

et al. 2011

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Abstract. Aldosterone, a steroid hormone, has traditionally been viewed as a key regulator of fluid and electrolyte homeostasis, as well as blood pressure, through the activation of mineralocorticoid receptor (MR). However, a number of studies performed in the last decade have revealed an important role of aldosterone/MR in the pathogenesis of renal injury. Aldosterone/MR-induced renal tissue injury is associated with increased renal inflammation and oxidative stress, fibrosis, mesangial cell proliferation, and podocyte injury, probably through genomic and non-genomic pathways. However, our preliminary data have indicated that acute administration of aldosterone or a selective MR antagonist, eplerenone, does not change blood pressure, heart rate, or renal blood flow. These data suggest that aldosterone/MR induces renal injury through mechanisms that are independent of acute changes in systemic and renal hemodynamics. In this review, we will briefly summarize the roles of aldosterone/MR in the pathogenesis of renal injury, focusing on the underlying mechanisms that are independent of systemic and renal hemodynamic changes.

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Mineralocorticoid Receptor Blockade Enhances the Antiproteinuric Effect of an Angiotensin II Blocker through Inhibiting Podocyte Injury in Type 2 Diabetic Rats

Cited by 43 publications

References 43 publications

Renoprotective Effect of Vasopressin V2 Receptor Antagonist Tolvaptan in Dahl Rats With End-Stage Heart Failure

Renoprotective Effect of Vasopressin V2 Receptor Antagonist Tolvaptan in Dahl Rats With End-Stage Heart Failure

Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

Pathophysiological Roles of Aldosterone and Mineralocorticoid Receptor in the Kidney

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