(Pro)renin receptor antagonist PRO20 attenuates nephrectomy‐induced nephropathy in rats via inhibition of intrarenal RAS and Wnt/β‐catenin signaling

Abstract

Introduction (Pro)renin receptor has emerged as a new member of the renin‐angiotensin system implicated in the pathogenesis of chronic kidney disease (CKD). Herein we report characterization of the therapeutic potential of (pro)renin receptor (PRR) antagonist PRO20 in 5/6 nephrectomy (5/6Nx) rats. Methods Male Wistar rats underwent 5/6Nx followed by treatment with vehicle or received daily injections of a PRR inhibitor PRO20 (700 μg/kg) via the 3 s.c. Sham group served as a control. Results As compared with the sham control, the 5/6Nx rats exhibited significant increases in proteinuria, glomerulosclerosis, tubular injury, and interstitial inflammation in the remnant kidneys. Treatment with PRO20 significantly attenuated these abnormalities, as evidenced by reduced expression of fibronectin, α‐SMA, collagen 1, TGF‐β1, IL‐6, IL‐8, IL‐1β, MCP‐1 and increased expression of E‐cadherin. Increased urinary/renal levels of renin activity, angiotensinogen (AGT), and Angiotensin II (Ang II) by 5/6Nx, which were all ameliorated by PRO20. Renal PRR, the secreted proteolytic fragment of PRR (sPRR) in renal and urinary, were all elevated in 5/6Nx rats. Moreover, our results revealed that renal Wnt3A and β‐catenin expression were upregulated during 5/6Nx, which were all attenuated by PRO20. Conclusions Overall we conclude that in vivo antagonism of PRR with PRO20 will improve 5/6Nx‐induced CKD mainly through inhibition of intrarenal RAS and Wnt/β‐catenin signaling pathway.

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor-Mediated Intrarenal Renin-Angiotensin System and Nox4-H2O2 Signaling

“…fPRR is highly expressed in renal tubules, and it has a potential role in renal RAS regulation [ 52 ]. Many studies have shown that fPRR could aggravate tissue damage, such as promoting the development of hypertension, diabetic nephropathy, and proteinuria nephropathy, by activating local RAS in tissues and activating the role of proinflammatory and profibrosis factors [ 34 , 53 – 56 ]. The data in the present study showed that fPRR inhibitors PRO20 and fPRR siRNA could significantly inhibit the AOPP-induced expression levels of AGT, ACE, AT1R, and Ang II in HK-2 cells.…”

“…RNA protocols and qRT-PCR were carried out as previously described [ 34 ]. Gene expression was normalized to GAPDH.…”

Soluble Prorenin Receptor: A Novel Biomarker for the Prediction of Renal Interstitial Fibrosis and Chronic Kidney Disease

“…An important nding of our study was the correlation of serum sPRR and the extent of renal interstitial brosis in various glomerular diseases using human biopsy samples. Although accumulating evidence suggest that PRR plays a role in renal brosis in various CKD animal models [16,17], the direct pro brotic effect of sPRR has been recently proven in human renal proximal tubular cell line (HK-2 cells) through the direct binding of AT 1 receptor to activate NF-κB [18]. In spite of this, the association of serum sPRR and renal brosis in human kidney samples are inconsistent in the literature.…”

The role of (pro)renin receptor and its soluble form in cardiovascular diseases

“…Other studies infused PRO20 into the renal medulla and found that it reduced sodium–water retention and attenuated Ang II-induced hypertension ( 77 ). It has also been reported to improve nephrectomy-induced nephropathy in rats by inhibiting Wnt/β-catenin signaling ( 126 ). It is exciting that PRO20 can inhibit Wnt/β-catenin signaling.…”