(Pro)renin receptor ((P)RR) has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of this study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. Anti-glomerular basement membrane (GBM) nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (% glomerular crescent: 62.1 ± 2.3%), accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4 and active β-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), the induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4 and active β-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the β-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/β-catenin pathways during the course of anti-GBM nephritis, and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.

中文翻译：

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（Pro）肾素受体通过肾小球肾炎中的ERK1 / 2和Wnt /β-catenin途径促进新月体形成。

（Pro）肾素受体（（P）RR）具有多种功能，但其在肾小球肾炎（GN）发病机理中的调控和作用定义不清。这项研究的目的是确定直接抑制肾素（DRI）的作用，并证明（P）RR在新月形GN进展中的作用。抗肾小球基底膜（GBM）肾炎大鼠模型发展为进行性蛋白尿（83.64±10.49 mg / day）和肾小球新月形成（肾小球新月％：62.1±2.3％），并伴有巨噬细胞浸润和单核细胞趋化蛋白的肾小球表达增加（ MCP）-1，（P）RR，磷酸化细胞外信号调节激酶（ERK）1/2，Wnt4和活性β-连环蛋白。DRI治疗可改善蛋白尿（20.33±5.88 mg /天），并显着减少肾小球新月体形成（20.9±2.6％），诱导巨噬细胞浸润，（P）RR，磷酸化ERK1 / 2，Wnt4和活性β-连环蛋白。此外，重组肾上腺素刺激的原代培养的壁上皮细胞显示出细胞增殖的显着增加。值得注意的是，尽管ERK1 / 2抑制剂PD98059或（P）RR特异性siRNA治疗消除了细胞增殖的升高，但DRI治疗并未消除该升高。此外，培养的肾小球系膜细胞显示出前肾素诱导的MCP-1表达增加。有趣的是，（P）RR或Wnt4特异性siRNA处理或β-catenin拮抗剂XAV939抑制了MCP-1表达的升高，而DRI则没有。这些结果表明（P）RR在抗GBM肾炎的过程中通过ERK1 / 2信号传导和Wnt /β-catenin途径调节肾小球的新月形成，