Functional renin receptors in renal mesangial cells

Huang, Yufeng; Border, Wayne A.; Noble, Nancy A.

doi:10.1007/s11906-007-0024-4

Cited by 26 publications

(19 citation statements)

References 57 publications

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“…When mice expressing human AGT were crossed with a line expressing a human mutant prorenin that was noncleavable, the elevation of ANG I content in the pituitary gland continued, suggesting that prorenin activation within the pituitary gland is not due to proteolytic cleavage of prorenin (22). Consistent with the data presented here using VSMCs, the nonproteolytic activation of prorenin in vivo in the double-transgenic mouse is likely mediated by the (p)RR, since (p)RR is abundant in the pituitary gland (11).…”

Section: Discussionsupporting

confidence: 82%

Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells

Zhang

Noble

Border³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10−7 M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.

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Section: Discussionsupporting

confidence: 82%

Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells

Zhang

Noble

Border³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…[40][41][42] It has been shown that (pro)renin binding to PRR provokes a rapid activation of mitogen-activated protein kinase and promotes matrix gene expression in an angiotensin II-independent fashion. 41,43,44 Furthermore, PRR is also an integral component of the Wnt receptor complex, and it augments Wnt signaling in a renin-independent manner. 45,46 Therefore, it is conceivable that some of the pathogenic effects of RAS components are independent of angiotensin II, which could account for the limited efficacy of current therapy through ACEIs and ARBs.…”

Section: Discussionmentioning

confidence: 99%

Multiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/β-Catenin Signaling

Zhou

Li²,

Hao³

et al. 2015

Journal of the American Society of Nephrology

204

222

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Activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. However, current anti-RAS therapy only has limited efficacy, partly because of compensatory upregulation of renin expression. Therefore, a treatment strategy to simultaneously target multiple RAS genes is necessary to achieve greater efficacy. By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor ( Extensive studies over the last several decades have established that activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. 1-3 RAS consists of several key components, including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1), and angiotensin II type 2 receptor (AT2). Many studies indicate that, after kidney injury, intrarenal RAS is markedly activated because of concurrent upregulation of multiple RAS genes. 4,5 RAS activation contributes to kidney and cardiovascular injury through a range of mechanisms. In addition to regulating BP and hemodynamics, 6,7 angiotensin II, the principal and active mediator of RAS, activates TGF-b1 and NF-kB signaling and directly promotes renal inflammation and fibrosis. 8-10 Studies using both genetic and pharmacologic approaches have confirmed the relevance and importance of RAS activation in the development and progression of CKD and cardiovascular disease. However, current anti-RAS therapy using ACE inhibitors (ACEIs) or angiotensin II receptor

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“…29,30 TGFβ1 is also a downstream target of AngII 31 and can be up-regulated by renin in mesangial cells through the pro(renin) receptor independently of AngII. [32][33][34] Treatments with aliskiren or valsartan significantly reduced the gene expression of TGFβ, CTGF and PAI-1 therefore preventing kidney injury in diabetes. In addition, at the doses used in this study aliskiren demonstrated a better effect than valsartan in preventing increase of proinflammatory cytokines TNF-α, MCP-1 and IL1-1β in the kidneys of the diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of aliskiren and valsartan in mice with diabetic nephropathy

Wang

Qiu²,

Howard³

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Aim: We investigated whether aliskiren, a direct renin inhibitor, provided protection in a model of diabetic nephropathy in mice and compared its protective effects to valsartan, an angiotensin II type 1 receptor blocker. Materials and methods: Hyperglycemia was induced with streptozotocin (STZ, 40 mg/kg/day × 5 days) injection in DBA/2J mice fed on a high fat diet. Mice were treated with either aliskiren (25 mg/kg/day) or valsartan (8 mg/kg/day) for 6 weeks. Results: Aliskiren and/or valsartan treatment significantly attenuated albuminuria, urinary nephrin excretion and glomerulosclerosis. Aliskiren and/or valsartan prevented reduction of podocin and WT1 protein abundance in diabetic mice. Aliskiren and/or valsartan significantly prevented increased expression of profibrotic growth factors (TGFβ, CTGF and PAI-1), proinflammatory cytokines (MCP-1, TNFα and IL-1β), endoplasmic reticulum (ER) stress markers (CHOP and XBP-1) and lipid accumulation in the kidney of diabetic animals. Aliskiren showed similar efficacy compared to valsartan therapy and dual treatment in some aspects has synergistic protective effects. Conclusion: Our study indicates that aliskiren and/or valsartan protects against diabetic kidney disease through multiple mechanisms, including decreasing podocyte injury, activation of profibrotic growth factors and proinflammatory cytokines, ER stress and accumulation of lipids.

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Functional renin receptors in renal mesangial cells

Cited by 26 publications

References 57 publications

Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells

Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells

Multiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/β-Catenin Signaling

Protective effects of aliskiren and valsartan in mice with diabetic nephropathy

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