Slowly Progressive, Angiotensin II–Independent Glomerulosclerosis in Human (Pro)renin Receptor–Transgenic Rats

Abstract

For defining the pathogenic effects of the (pro)renin receptor-transgenic rat, strains that overexpressed the human receptor were generated. Although transgenic rats were normotensive and euglycemic and had a renal angiotensin II (AngII) level that was comparable to that of wild-type rats, transgenic rats developed proteinuria with aging and significant glomerulosclerosis at 28 wk of age. In kidneys of 28-wk-old transgenic rats, mitogen-activated protein kinases (MAPK) were activated without recognizable tyrosine phosphorylation of the EGF receptor, and expression of TGF-␤1 was enhanced. In vivo infusion of the (pro)renin receptor blocker peptide (formerly handle region decoy peptide) significantly inhibited the development of glomerulosclerosis, proteinuria, MAPK activation, and TGF-␤1 expression in the kidneys, but the angiotensin-converting enzyme inhibitor did not attenuate these changes despite a significant decrease in the renal AngII level. In addition, recombinant rat prorenin stimulated MAPK activation in the human receptor-expressed cultured cells, but human receptor was unable to evoke the enzyme activity of rat prorenin. Thus, human (pro)renin receptor elicits slowly progressive nephropathy by AngII-independent MAPK activation in rats. This study clearly provided in vivo evidence for the AngII-independent MAPK activation by human (pro)renin receptor and induction of glomerulosclerosis with increased TGF-␤1 expression. T he (pro)renin receptor is a 350 -amino acid residue protein that has a single transmembrane domain and is expressed in various organs. It binds specifically to renin and prorenin and evokes nonproteolytic activation of prorenin (1), but a recent study showed that the enzymatic activity of the renin in the soluble phase and the receptorbound renin was similar (2). When the receptor binds inactive prorenin of the same species, the receptor-bound prorenin gains its enzyme activity (ability to generate angiotensin I [AngI]) without proteolytic cleavage of the prosegment of prorenin (3) presumably by a conformational change. This nonproteolytic activation of prorenin was considered to play a pivotal role in nephropathy and cardiomyopathy in animals model of diabetes and hypertension (4 -6). More recent studies demonstrated that renin upregulates TGF-␤1 and matrix proteins through a (pro)renin receptor without involving angiotensin II (AngII) in mesangial cells (7) and that the prorenin binding to a (pro)renin receptor plays a key role in the development of diabetic nephropathy in AngII type 1 receptor-deficient mice (8). These observations suggest that the (pro)renin receptor may elicit intracellular signals independent of the renin-angiotensin system (RAS), although it can also evoke the enzyme activity of prorenin.Nguyen et al.(1) produced in vitro evidence to suggest that the AngII-independent mechanisms of (pro)renin receptor action may involve a stimulation of tyrosine phosphorylation that leads to activation of the mitogen-activated protein kinase (MAPK). However, it is difficult to ...

Biochemical properties of renin and prorenin binding to the (pro)renin receptor

“…49 Human HRP prevented the proteinuria and glomerulosclerosis that developed in human (P)RR transgenic rats. 31 Blockade of prorenin activation using decoy peptide in spontaneously hypertensive rats with high-salt diet has been reported by Susic et al, 50 who also showed reduction of serum creatinine level, decreased left ventricular mass and fibrosis, improved left ventricular function by treating these rats with the decoy.…”

“…[25][26][27][28][29] The (P)RR itself has been observed to be associated with many pathophysiology of diseases. [30][31][32][33][34][35] Considering the physiological importance of the (P)RR, this review is focused on the studies regarding the binding mechanism of renin/prorenin to (P)RR on the basis of their biochemical aspects.…”

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

“…Aberrant activation of these pathways has led to heart fibrosis, renal fibrosis, glomerulosclerosis, cystic disease and diabetic nephropathy. 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.…”

“…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?…”

Qualitative and quantitative analyses of (pro)renin receptor in the medium of cultured human umbilical vein endothelial cells

“…[7][8][9] Overexpressed (P)RR in smooth muscle cells causes elevated blood pressure and increased heart rate, 10 and glomerulosclerosis and proteinuria have been reported in transgenic models in which (P)RR is overexpressed. 11 Mutation of the (P)RR gene is associated with X-linked mental retardation in humans. 12 We have reported the expression and purification of full-length rat (P)RR using a baculovirus expression system.…”