Prorenin Induces Intracellular Signaling in Cardiomyocytes Independently of Angiotensin II

Abstract

Abstract-Tissue accumulation of circulating prorenin results in angiotensin generation, but could also, through binding to the recently cloned (pro)renin receptor, lead to angiotensin-independent effects, like p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI)-1 release. Here we investigated whether prorenin exerts angiotensin-independent effects in neonatal rat cardiomyocytes. Polyclonal antibodies detected the (pro)renin receptor in these cells. Prorenin affected neither p42/p44 MAPK nor PAI-1. PAI-1 release did occur during coincubation with angiotensinogen, suggesting that this effect is angiotensin mediated. Prorenin concentrationdependently activated p38 MAPK and simultaneously phosphorylated HSP27. The latter phosphorylation was blocked by the p38 MAPK inhibitor SB203580. Rat microarray gene (nϭ4800) transcription profiling of myocytes stimulated with prorenin detected 260 regulated genes (PϽ0.001 versus control), among which genes downstream of p38 MAPK and HSP27 involved in actin filament dynamics and (cis-)regulated genes confined in blood pressure and diabetes QTL regions, like Syntaxin-7, were overrepresented. Quantitative real-time RT-PCR of 7 selected genes (Opg, Timp1, Best5, Hsp27, Col3a1, and Hk2) revealed temporal regulation, with peak levels occurring after 4 hours of prorenin exposure. This regulation was not altered in the presence of the renin inhibitor aliskiren or the angiotensin II type 1 receptor antagonist eprosartan. Finally, pilot 2D proteomic differential display experiments revealed actin cytoskeleton changes in cardiomyocytes after 48 hours of prorenin stimulation. In conclusion, prorenin exerts angiotensinindependent effects in cardiomyocytes. Prorenin-induced stimulation of the p38 MAPK/HSP27 pathway, resulting in alterations in actin filament dynamics, may underlie the severe cardiac hypertrophy that has been described previously in rats with hepatic prorenin overexpression. (Hypertension. 2006;48:564-571.)

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

“…A major amount of the receptor is located on intracellular vesicles, whereas only a fraction is found on the plasma membrane. 91,108 In contrast, a predominance of (P)RR expression was noted at the luminal surface of rat kidney collecting duct intercalated cells. 102 The full-length (P)RR, after trafficking to the Golgi, is cleaved by protease furin to liberate a 28 kDa fragment called soluble (P)RR and the 8.9 kDa fragment.…”

“…In cardiomyocytes, (pro)renin-bound (P)RR stimulates p38 MAPK, heat shock protein 27 and phosphatidylinositol-3-kinase-85. [89][90][91][92][93][94] Thus, diabetic nephropathy and retinopathy, and cardiac fibrosis develop mainly by the non-proteolytic activation of (pro)renin bound to the (P)RR. 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 ).…”

“…113 The v-H + -ATPase is a multisubunit complex molecule that is organized into the V 1 (eight subunits) and V O (six subunits) sectors and two accessory subunits (Ac45 and (P)RR/ATP6ap2) localized mainly within intracellular compartments and to a minor part at the plasma membrane. 91,108,112 The (P)RR/ATP6AP2 senses the acidity levels of the intracellular compartments and accordingly regulates v-H + -ATPase activity. 112 The disruption of pH homeostasis in v-H + -ATPase mutants showed lethality in various organisms.…”

“…6,112,[130][131][132][133] Overexpression of the (P)RR in the rat and mouse resulted in hypertension and fibrotic effects. 91,111,130 This raises several questions. How does the binding of prorenin to the (P)RR affect the function of v-H + -ATPase and contribute to generation of Ang (hypertension) and trigger MAPK signaling pathways (glomerulosclerosis, heart fibrosis) in a renin-independent manner?…”

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

“…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.…”