(Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation

Matavelli, Luis C.; Huang, Jiqian; Siragy, Helmy M.

doi:10.1111/j.1440-1681.2009.05292.x

Cited by 98 publications

(101 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, receptor-bound prorenin may be elevated by an increase in prorenin levels and/or an increase in (P)RR levels, 13 thereby contributing to the development of nephropathy in diabetic animals. These findings were recently confirmed by Matavelli et al 14 The direct administration of HRP to the renal cortical interstitium of diabetic rats significantly decreased urinary albumin excretion and the renal production of tumor necrosis factora and interleukin-1b. A similar improvement in nephropathy after HRP treatment was observed in streptozotocin-induced diabetic rats in which nephropathy had already developed 15 and in angiotensin IItype Ia-receptor-deficient mice with streptozotocin-induced diabetes.…”

Section: Suggestions From Animal Models Of Diabetessupporting

confidence: 74%

Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

et al. 2009

View full text Add to dashboard Cite

Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology. Hypertension Research (2010) 33, 177-180; doi:10.1038/hr.2009 published online 18 December 2009 Keywords: angiotensin; ATP6ap2; handle region peptide; prorenin; vacuolar H + -ATPase INTRODUCTIONThe pathophysiological roles of the (pro)renin receptor ((P)RR) are a growing concern because numerous experimental studies conducted since this receptor was first discovered in 2002 1 have suggested that the pro(renin) receptor has its own intracellular signaling pathways and is involved in the tissue renin-angiotensin system. However, the clinical relevance of the human (P)RR remains uncertain because only a few clinical studies examining the (P)RR have been performed. In this review article of previous studies and new findings, we attempt to elucidate the possible role of the (P)RR in humans. SUGGESTIONS FROM IN VITRO STUDIESThe (P)RR was first reported to be capable of binding both renin and prorenin in vitro. 1 However, Batenburg et al. 2 showed that prorenin, but not renin, was capable of binding to the (P)RR in cultured vascular smooth muscle cells, suggesting that prorenin is an endogenous agonist of the (P)RR. In addition, Nabi et al. 3 provided clear evidence that receptor-bound prorenin gains 'renin activity' without undergoing the proteolytic cleavage of the prosegment of prorenin as a result of a conformational change, although the enzymatic activity of receptor-bound renin is similar to that of free renin. On the basis of these findings, renin may be an endogenous inhibitor for the binding of prorenin to the (P)RR.Stimulation of the (P)RR by renin and prorenin reportedly results in the activation of intracellular signaling pathways, including MAP kinases, in mesangial cells, 4-6 vascular smooth muscle cells, 7 cardiomyocytes 8 and renal tubular epithelial cells. 9 However, the significance of the (P)RR-dependent intracellular signals in vivo remains undetermined. SUGGESTIONS FROM ANIMAL MODELS OF DIAB...

show abstract

Section: Suggestions From Animal Models Of Diabetessupporting

confidence: 74%

Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Additionally, several clinical and animal studies have indicated that inflammatory cytokines play an important role in the development and progression of diabetic nephropathy (29,30). It was demonstrated that diabetes increased proinflammatory renal production, including TNF-α, IL-1β and IL-6 in the circulating, and urinary excretion (31)(32)(33). Another important finding in the current study is that the levels of MDA and protein carbonyl group and protein expression of MnSOD and CuZn-SOD in renal tissues as well as TNF-α, IL-1β and IL-6 in plasma were remarkably increased in the vehicle and diabetic groups compared to non-diabetic rats.…”

Section: Discussionmentioning

confidence: 99%

Autologous transplantation of adipose-derived mesenchymal stem cells ameliorates streptozotocin-induced diabetic nephropathy in rats by inhibiting oxidative stress, pro-inflammatory cytokines and the p38 MAPK signaling pathway

et al. 2012

View full text Add to dashboard Cite

Abstract. Diabetic nephropathy is the leading cause of endstage renal disease. The aim of this study was to investigate the renoprotective effects of autologous transplantation of adiposederived mesenchymal stem cells (ADMSCs) and to delineate its underlying mechanisms of action in diabetic nephropathy. Diabetes was induced in adult male Sprague-Dawley rats by streptozotocin (STZ) injection. ADMSCs were administered intravenously 4 weeks after STZ injection and metabolic indices and renal structure were assessed (12 weeks). Markers of diabetes including blood glucose, cholesterol, triglycerides, urea nitrogen and creatinine were measured. Renal pathology, levels of oxidative stress and the expression of pro-inflammatory cytokines and the MAPK signaling pathway members were also determined. Autologous transplantation of ADMSCs significantly attenuated common metabolic disorder symptoms associated with diabetes. Furthermore, ADMSC administration minimized pathological alterations, reduced oxidative damage and suppressed the expression of pro-inflammatory cytokines in the renal tissues of diabetic rats. ADMSC transplantation also decreased the expression of p-p38, p-ERK and p-JNK, which are all important molecules of the MAPK signaling pathway. In conclusion, we provide experimental evidence demonstrating that autologous transplantation of ADMSCs can be used therapeutically to improve metabolic disorder and relieve renal damage induced by diabetes, and that the key mechanisms underlying the positive therapeutic impact of ADMSC treatment in kidneys could be due to the suppression of inflammatory response and oxidative stress. IntroductionDiabetic nephropathy is a major microvascular complication in patients with diabetes and remains the leading cause of chronic kidney disease, accounting for approximately a half of all end-stage renal disease worldwide (1,2). The key pathologic features of diabetic nephropathy include microalbuminurea, mesangial cell (MC) hypertrophy, thickened glomerular and tubular basement membrane, tubulointerstitial fibrosis, and low grade of renal inflammation. It is now well recognized that the pathogenesis of diabetic nephropathy is multifactorial. Over the last decade, diverse pathological mechanisms have been proposed to be involved in the onset and development of diabetic nephropathy, such as genetic and hemodynamic factors, oxidative stress and cytokine signaling (3,4). Nowadays, therapies for diabetic nephropathy have been limited to drugs that improve blood pressure or control blood glucose levels. However, these therapies are not very effective in blocking renal damage and co-treatment with renoprotective drugs often leads to toxicity and reduction in efficacy (5,6). There is thus an imperative need to develop effective therapeutic strategies to preserve normal renal function or to halt the progression of diabetic nephropathy.Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitor cells that can differentiate into a variety of cell types, including osteoblasts, ch...

show abstract

“…An upregulation in (pro)renin and (P)RR levels contributing to the development of nephropathy in diabetic animals has been reported by many investigators (reviewed in Balakumar and Jagadeesh 26 ). Recently, Matavelli et al 95 extended these mechanisms suggesting that the renal (pro)renin and (P)RR axis promotes diabetic nephropathy by significantly increasing the amounts of pro-inflammatory cytokines. The handle region peptide (HRP), a putative blocker of the (P)RR, could efficiently block glomerulosclerosis, 86,88,95,96 while RAS inhibitors were unable to prevent end-stage organ damage associated with diabetes.…”

Section: Implication Of (P)rrs In Pathologic Conditionsmentioning

confidence: 98%

“…Recently, Matavelli et al 95 extended these mechanisms suggesting that the renal (pro)renin and (P)RR axis promotes diabetic nephropathy by significantly increasing the amounts of pro-inflammatory cytokines. The handle region peptide (HRP), a putative blocker of the (P)RR, could efficiently block glomerulosclerosis, 86,88,95,96 while RAS inhibitors were unable to prevent end-stage organ damage associated with diabetes. 97,98 However, not all investigators were able to reproduce the inhibitory effects of HRP either in vivo or in vitro.…”

Section: Implication Of (P)rrs In Pathologic Conditionsmentioning

confidence: 98%

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

Balakumar

Jagadeesh

2011

Hypertens Res

View full text Add to dashboard Cite

The renin-angiotensin system and Wnt/frizzled receptor signaling pathways are important in the development of essential organs, and their aberrant activation results in cardiovascular and renal pathologies. The (pro)renin receptor ((P)RR)-bound (pro)renin is enzymatically active generating angiotensin-II and activating mitogen-activated protein kinases, leading to cell proliferation and to upregulation of profibrotic genes expression, resulting in end-organ damage. The (P)RR does more than bind to (pro)renin, because it is functionally linked to the vacuolar-H + -ATPase (v-H + -ATPase) that regulates pH of cellular and intracellular vesicles, and to Wnt signaling. This signaling pathway is essential for cell survival, embryonic development and has had a role in various disease states as evidenced by mutation or genetic ablation of the (P)RR gene. This suggests two types of functions of (P)RRs, first one as a receptor for (pro)renin and second one as an accessory subunit of the v-H + -ATPase and a cofactor of the Wnt/Fz receptor complex. This review will discuss both of these functions of (P)RRs thereby giving new perspectives as to the roles of (P)RRs in cardiovascular and renal pathologies.

show abstract

(Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation

Cited by 98 publications

References 37 publications

Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

Autologous transplantation of adipose-derived mesenchymal stem cells ameliorates streptozotocin-induced diabetic nephropathy in rats by inhibiting oxidative stress, pro-inflammatory cytokines and the p38 MAPK signaling pathway

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

Contact Info

Product

Resources

About