Dose-dependent titration of prorenin and blood pressure in Cyp1a1ren-2 transgenic rats: absence of prorenin-induced glomerulosclerosis

Peters, Barbara; Grisk, Olaf; Becher, Bertram; Wanka, Heike; Kuttler, Beate; Lüdemann, Jan; Lorenz, Gerd; Rettig, Rainer; Mullins, John J.; Peters, Jörg

doi:10.1097/hjh.0b013e3282f0ab66

Cited by 90 publications

(116 citation statements)

References 27 publications

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“…Similarly, in transgenic animals, where circulating prorenin was 200 times more than renin failed to cause cardiac or kidney fibrosis but were hypertensive, and the increase in blood pressure could be antagonized by Ang-converting enzyme inhibitors. 105,106 The discrepancy in the effect of HRP, and the absence of an end-organ damage in pregnancy and transgenic animals are probably because of: (a) decreased expression of cathepsin enzyme in kidneys of diabetic rats, 107 (b) absence of non-proteolytic activation of prorenin because of downregulation of (P)RR via activation of the transcription factor promyelocytic zinc-finger pathway, 108 (c) subcellular localization and intracellular processing of (P)RRs and their association with v-H + -ATPase, 107,109 (d) the varying affinity of the molecular forms of (P)RRs for (pro)renin 109 and (e) the difference in distribution of full-length receptor to soluble receptor 107 in a disease condition. A recent report suggests that angiotensinogen is cleaved differently by free renin and renin bound to (P)RR.…”

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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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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“…However, it must be noted that the concept of prorenininduced tissue injury is not fully established; in two models of prorenin over-expressing mice, cardio-renal damage was not observed. 128,129 The potential clinical significance of the (P)RR is highlighted in a set of studies by Ichihara and coworkers (reviewed elsewhere 130 ) that suggest a central function for this receptor in the pathogenesis of DN. This body of work is particularly provocative because the authors have reported dramatic benefits in STZ-diabetic rats with a putative (P)RR blocker.…”

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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“…In addition, an elevated circulating prorenin level did not cause organ damage in the rats overexpressing prorenin. 24,25 Thus, the majority of soluble (P)RRs may stay in the extracellular space, and only a few are present in the plasma probably because of digestion by plasma protease. If the prorenin-binding soluble (P)RR is enzymatically active, the presence of soluble (P)RR in renal extracellular space may explain why renal interstitial levels of angiotensin II are higher than plasma levels of angiotensin II.…”

Section: New Insights Into the (P)rrmentioning

confidence: 99%

“…21 Recent studies have shown that an increase in circulating prorenin level is not associated with organ damage. 24,25 As elevated levels of renin and prorenin downregulate the expression of the (P)RR through a negative feedback system, 26,27 organ damage would develop via a (P)RR-independent mechanism under conditions with a simple increase in circulating prorenin level. Thus, HRP would have no effect on animal models with a simple increase in circulating prorenin level.…”

mentioning

confidence: 99%

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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Dose-dependent titration of prorenin and blood pressure in Cyp1a1ren-2 transgenic rats: absence of prorenin-induced glomerulosclerosis

Cited by 90 publications

References 27 publications

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

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

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

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

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