Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren

Schefe, Jan H.; Neumann, Christian; Goebel, Matthias; Danser, Jan; Kirsch, Sebastian; Gust, Ronald; Kintscher, Ulrich; Unger, Thomas; Funke-Kaiser, Heiko

doi:10.1097/hjh.0b013e3283060f2e

Cited by 93 publications

(89 citation statements)

References 35 publications

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“…32 The plasma prorenin levels in diabetic patients were significantly higher than those in non-diabetic patients. Nevertheless, arterial (P)RR expression was similar in diabetic and non-diabetic patients, suggesting that the negative feedback mechanism of the (P)RR observed in cultured cells 26,27 does not work in diabetic patients. In addition, multiple regression analyses showed a significant association with a large coefficient between the arterial mRNA level of the (P)RR and the arterial mRNA level of angiotensin-converting enzyme; this significant association disappeared in patients who had been treated with inhibitors of the renin-angiotensin system.…”

Section: Arterial Mrna Levels In Patients With Stage 5 Chronic Kidneymentioning

confidence: 84%

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

et al. 2009

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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...

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Section: Arterial Mrna Levels In Patients With Stage 5 Chronic Kidneymentioning

confidence: 84%

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

et al. 2009

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“…Aliskiren does not inhibit binding of (pro)renin to the (P)RR, 87,118 nor does it prevent (pro)renin-induced cell signaling. 87,118,120 However, in STZ-diabetic mRen-2 rats treated with aliskiren for 10 weeks, in situ hybridization on renal sections revealed a clear reduction in gene expression of the (P)RR in the glomeruli and tubular cells compared with vehicle-control diabetic mRen-2 rats. 87 Interestingly, in vitro studies showed that aliskiren did not affect gene expression of (P)RR in mesangial cells.…”

Section: Aliskiren Localizes In the Kidneymentioning

confidence: 91%

“…109 Furthermore, on binding to the (P)RR, prorenin, which is normally inactive, becomes catalytically active (it can cleave Aogen to form Ang I), possibly because of a conformational change induced by the binding. 109,[114][115][116] The Ang IIindependent effects of (P)RR stimulation include activation of extracellular signal-regulated kinase1/2, 109,117,118 and heat shock protein 27 119 and phosphatidylinositol-3 kinase p85a 120 pathways. The production of TGF-b and plasminogen-activator-1 is also increased, as are gene expression and production of collagen I and fibronectin, respectively.…”

Section: Aliskiren Localizes In the Kidneymentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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“…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. 97,99 In diabetic subjects, prorenin to active renin ratio is very high.…”

Section: Implication Of (P)rrs In Pathologic Conditionsmentioning

confidence: 99%

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

Balakumar

Jagadeesh

2011

Hypertens Res

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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.

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Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren

Cited by 93 publications

References 35 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

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

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

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