Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells

Abstract

Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10−7 M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.

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

“…25 It is interesting to note that this receptor has also been found to activate prorenin. [25][26][27][28][29] After binding to the (P)RR, prorenin undergoes a conformational change in the prosegment region, thus opening the active site accessible to the substrate angiotensinogen (Figures 1 and 2). The (P)RR mRNA has been reported to express in many organs, for example the kidney, heart, brain, eye, adipose tissue and vascular smooth muscle cells, 25,34 and thus it may help to accumulate renin and prorenin locally in tissues even though lacking components of RAS, that is, in the heart and vasculature wall.…”

“…Batenburg et al 27 found a similar activation of human prorenin by binding to the human (P)RR with 6.0 nmol l À1 of K D , using the receptor expressed in smooth muscle cells of transgenic rat for this receptor. Zhang et al 28 reported the activation of rat prorenin after binding to rat (P)RR expressed in the cultured vascular smooth muscle cells.…”

“…24 The (pro)renin receptor, 25 (P)RR, a new player in the RAS components, binds both renin and prorenin. [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.…”

Association of (pro)renin receptor gene polymorphisms with lacunar infarction and left ventricular hypertrophy in Japanese women: the Ohasama study

“…[5][6][7][8][9][10][11][12] In vitro studies using small interfering RNA have been demonstrated that knockdown of (P)RR suppressed fibrotic factor release in rat cultured vascular smooth muscle cells and mesangial cells. 28,29 Moreover, the (P)RR has been reported to cause nonproteolytic activation of prorenin and directly activate intracellular signaling pathways independently of the RAS. 1,30 Saris et al 31 reported that prorenin-induced intracellular signaling in cardiomyocytes independently of angiotensin II and suggested that prorenin directly affected cardiac growth and development via the (P)RR-mediated activation of ERK1/2.…”

Biochemical, Structural and Pathophysiological Aspects of Prorenin and (Pro)renin Receptor

“…It is reported that (P)RR expressed in VSMCs in human (P)RR transgenic rats can be recycled between intracellular compartment and cell membrane (Batenburg et al, 2007). The (P)RR is also localized on the membrane of stromal adipose cells (Achard et al, 2007), in the neurons of neonatal rats (Shan et al, 2008), on COS-7 cells (Nabi et al, 2007), in glomerular mesangial cells, the subendothelium of renal arteries, podocytes, and distal nephron cells (Nguyen et al, 2002(Nguyen et al, , 1996(Nguyen et al, , 1998 of human and rat kidneys; U937 monocytes (Feldt et al, 2008b) and also in intracellular compartments or on the surface of vascular smooth muscle cells (VSMCs) Zhang et al, 2008), in endoplasmic reticulum (Schefe et al, 2006;Yoshikawa et al, 2011), golgi apparatus Yoshikawa et al, 2011), cytosol Cousin et al, 2009) and found in plasma (Cousin et al, 2009). Expression of (P)RR is also categorized in the subfornical organ (SFO), paraventricular nucleus, the supraoptic nucleus, the nucleus of the tractus solitarius (NTS), or the rostral ventrolateral medulla regions of brain that were believed to be involved in the central regulation of cardiovascular function and volume homeostasis , in the frontal lobe of human brain and pituitary (Takahashi et al, 2010).…”