(Pro)renin receptors: are they biologically relevant?

Danser, AH Jan

doi:10.1097/mnh.0b013e3283196aaf

Cited by 30 publications

(38 citation statements)

References 48 publications

(49 reference statements)

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“…32 In humans, klotho expression also decreases in CKD patients, 33 and also has protective renal effects by protecting cells/ tissues from oxidative stress and apoptosis. 29 In our study, we demonstrated that direct renin inhibition significantly increased klotho expression in vitro and in vivo. The increased expression of klotho gene might further protect chronic ischemic renal injury in animals undergoing aliskiren treatment.…”

Section: Discussionsupporting

confidence: 51%

“…28 In vivo, (P)RR transgenic rats develop glomerulosclerosis and hypertension in the absence of changes to renin or angiotensin levels. 29 Various animal models demonstrated that inhibition of pro-renin binding to the (P)RR can prevent or even abolish the development of cardiac fibrosis and diabetic nephropathy. 30 In our study, aliskiren significantly decreased renal (P)RR mRNA expression in chronic ischemia.…”

Section: Discussionmentioning

confidence: 99%

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Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

et al. 2011

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Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, Po0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, Po0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

et al. 2011

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“…104 Aliskiren, prorenin and the (pro)renin receptor The recent discovery of a receptor for renin and prorenin, the (P)RR, 105 has added an important new dimension to the tissue RAAS. [106][107][108] In the kidney, gene and/or protein expression of the (P)RR has been reported in the glomerular mesangium, 109 vascular wall 87,109 and tubular cells. 87,110 Gene and protein expression for the (P)RR has also been reported in podocytes.…”

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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“…6): (i) increases catalytic activity of the PRR-bound prorenin to produce Ang I [44]; and (ii) activates MAP kinases independently of Ang II [45]. When prorenin binds PRR, a conformational change occurs in the prorenin molecule conferring full enzymatic activity and the ability to produce Ang I without undergoing proteolytic cleavage [reviewed in [46]]. Prorenin makes up 70-90% of total circulating renin [47], but it will not be converted to renin [48], which is synthesized only in the kidney.…”

Section: Prorenin and Renin Receptormentioning

confidence: 99%

The Renin Angiotensin System and the Metabolic Syndrome~!2010-02-12~!2010-04-19~!2010-06-25~!

Wang¹,

Li²,

Takahashi³

2010

TOHYPERJ

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(Pro)renin receptors: are they biologically relevant?

Cited by 30 publications

References 48 publications

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

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

The Renin Angiotensin System and the Metabolic Syndrome~!2010-02-12~!2010-04-19~!2010-06-25~!

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