Prorenin receptor mediates inflammation in renal ischemia

Abstract

We hypothesized that PRR contributes to renal inflammation in the 2-kidney, 1-clip (2K1C) renal ischaemia model. Male Sprague-Dawley rats were fed normal sodium diet. Blood pressure (BP) was obtained on days 0 and 28 after left renal artery clipping that reduced renal blood flow by 40%. Renal expression of TNF-α, COX-2, NF-κB, IL-1β, MCP-1 and collagen type I were assessed in sham and 2K1C rats with or without left renal administration of scramble or PRR shRNA. At baseline, there were no differences in BP. Compared to sham, MAP significantly increased in clipped animals (sham 102 ± 1.9 vs 2K1C 131.8 ± 3.09 mmHg, P < .05) and was not influenced by scramble or PRR shRNA treatment. Compared to sham and contra lateral (non-clipped) kidney, there was upregulation in mRNA and protein expression of PRR (99% and 45%, P < .01), TNF-α (72% and 50%, P < .05), COX-2 (72% and 39%, P < .05), p-NF-κB (92%, P < .05), MCP-1 (87%, P < .05) and immunostaining of collagen type I in the clipped kidney. These increases were not influenced by scramble shRNA. Compared to 2K1C and scramble shRNA, PRR shRNA treatment in the clipped kidney significantly reduced the expression of PRR (62% and 57%, P < .01), TNF-α (51% and 50%, P < .05), COX-2 (50% and 56%, P < .05), p-NF-κB by 68% (P < .05), MCP-1 by 73% (P < .05) and collagen type I respectively. Ang II was increased in both kidneys and did not change in response to scramble or PRR shRNA treatments. We conclude that PRR mediates renal inflammation in renal ischaemia independent of blood pressure and Ang II.

The Pathological Role of Pro(Renin) Receptor in Renal Inflammation

“…Targeted knockdown of PRR in the clipped kidney attenuated the expression of IL-1β, TNF-α, COX-2, and NF-ҡB indicating the intricate and direct interaction between PRR and renal inflammation. 5 PRR also plays an important role in is renal dysfunction associated with diabetes. Diabetic nephropathy is characterized by increased renal inflammation and fibrosis and is strongly associated with glomerular injury leading to the development of the end-stage renal disease.…”

“…Targeted knockdown of PRR in the clipped kidney attenuated the expression of IL-1β, TNF-α, COX-2, and NF-ҡB indicating the intricate and direct interaction between PRR and renal inflammation. 5 …”

“…1,2 Binding of renin/prorenin to PRR has been shown to increase the catalytic activity of renin by about four-to fivefold and induce a signaltransduction cascade leading to vasoconstriction, sodium, and water reabsorption, cell growth, proliferation, and inflammatory responses. [3][4][5] It is expressed in almost all of the body tissues including smooth muscle, kidney, liver, brain, testis, lung, heart, and adipose tissue, 3,6,7 and activation of PRR has been linked to upregulation and activation of mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases (ERK). 8 Expression/Signaling of (Pro)Renin Receptor (PRR) in the Kidney (Pro)renin receptor (PRR), a new member of the renin-angiotensin system (RAS) encoded by ATPase H(+)-transporting lysosomal accessory protein 2 (ATP6AP2) was first cloned in mesangial cells.…”

The interaction partners of (pro)renin receptor in the distal nephron

“…However, a similar effect of PRR on COX-2 expression has been observed in the renal medulla. 22,38 Gonzalez et al for the first time reported that COX-2 was colocalized with PRR in intercalated cells of CDs in the rat kidney. 22 In primary cultured rat renal IMCD cells, both prorenin and Ang II treatment enhanced the COX-2 and pERK1/2 expressions.…”

“…22 A similar effect was observed in the 2-kidney, 1-clip (2K1C) renal ischemia rats, where PRR shRNA treatment significantly attenuated the COX-2 expression in kidney but the Ang II levels in the renal interstitial fluid were unaffected. 38 In addition, PGE 2 augments prorenin/renin protein expression in cultured M-1 CD cells, subsequently activates PRR to stimulate the COX-2 expression and further PGE 2 synthesis, 39 then increases the expression of plasminogen activator inhibitor (PAI-1) and connecting tissue growth factor (CTGF) via EP 4 receptor and TGF-β receptor-dependent Smad pathway. 16 The binding of prorenin to PRR not only induces the non-proteolytic activation of prorenin to increase its enzymatic activity, but also triggers the activation of ERK1/2 5 .…”