Regression of Nephropathy Developed in Diabetes by (Pro)renin Receptor Blockade

Abstract

Activation of prorenin by (pro)renin receptor stimulates the tissue renin-angiotensin system and plays a significant role in the development of nephropathy in diabetic animals. This study examined whether (pro)renin receptor blockade inhibits the progression of nephropathy that has already developed in diabetic rats. Seventeen-week-old heminephrectomized streptozotocin-induced diabetic rats with an increased urinary protein excretion and a significant glomerulosclerosis had been treated for 12 wk with the (pro)renin receptor blocker (PRRB), angiotensin-converting enzyme inhibitor (ACEi), or vehicle peptide by using subcutaneously implanted osmotic minipumps. At the end of observation, in diabetic rats that were treated with vehicle, urinary protein excretion was progressively increased and a significant progression of glomerulosclerosis was observed. In diabetic rats that were treated with PRRB, however, no further increase in urinary protein excretion or glomerulosclerosis was observed, but 12-wk treatment with ACEi only attenuated further increases in urinary protein excretion and glomerulosclerosis. The enhanced expression of activated prorenin was observed in the kidneys of diabetic rats that were treated with vehicle, whereas it was markedly suppressed in the kidneys of diabetic rats that were treated with PRRB but not ACEi. These results suggest that (pro)renin receptor blockade does not only inhibit the progression of nephropathy but also reverses the glomerulosclerosis that has already developed in diabetic rats. Prorenin has a prosegment of 43 amino acid residues that are attached to the N terminus of mature (active) renin, and the prosegment folds into the active site cleft of mature renin to prevent catalytically productive interaction with angiotensinogen. When a prorenin-binding protein interacts with the "handle region" of the prorenin prosegment, the prorenin molecule undergoes a conformational change to an enzymatically active state. 1 This phenomenon is called nonproteolytic activation, and recent studies found that such binding proteins include the (pro)renin/renin receptor. 2,3 We recently found that nonproteolytic activation of prorenin plays a pivotal role in the activation of the renal renin-angiotensin system (RAS) and the development of nephropathy in diabetic rats and that the (pro)renin receptor blocker (PRRB; formerly handle region decoy peptide) clearly prevented the development of nephropathy and suppressed an increase of renal angiotensins. 3 However, whether nonproteolytically activated prorenin is also involved in the progression of nephropathy that had already developed in diabetic rats remained undetermined.This study was designed to determine whether PRRB is able to inhibit the progression of nephropathy after its development in diabetic rats. Prorenin prosegment has a tetrameric segment termed "gate region" (GR; S 7 FGR 10 ) that is not accessible by its

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

“…These findings were recently confirmed by Matavelli et al 14 The direct administration of HRP to the renal cortical interstitium of diabetic rats significantly decreased urinary albumin excretion and the renal production of tumor necrosis factora and interleukin-1b. A similar improvement in nephropathy after HRP treatment was observed in streptozotocin-induced diabetic rats in which nephropathy had already developed 15 and in angiotensin IItype Ia-receptor-deficient mice with streptozotocin-induced diabetes. 16 These latter results indirectly suggested that (P)RR-dependent intracellular signals may also contribute to the development and progression of diabetic nephropathy.…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…The same group has shown that administration of handle region peptides to diabetic rats can also cause regression of established diabetic nephropathy. 145 In cultured mesangial cells, it has been suggested that high glucose-induced prorenin upregulation leads to the production of inflammatory cytokines, such as interleukin-1b and cyclooxygenase-2 (Huang and Siragy 146 ). In the retinal vasculature of diabetic mice, Satofuka et al 147 have shown that handle region peptides, also called (P)RR blockers (PRRBs), reduced leukostasis to a greater extent than the AT1-R blocker losartan in wild-type mice and also reduced leukostasis in AT1A receptor gene knockout mice.…”

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

“…This is supported from studies where the excessive non-proteolytic activation of (P)RR-bound prorenin has a major role in diabetic nephropathy and retinopathy, and cardiac fibrosis. 86,88,[100][101][102] As a result of high prorenin level in these diseases, the HRP blocked prorenin binding to the (P)RR (enzymatic activation) and non-proteolytic activation of prorenin by (P)RR. This suggests overexpression of (P)RRs and a predominant role of RAS in these disease conditions.…”

“…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. 109 Soluble (P)RR is found in both rat and human plasma 109 and human urine.…”