Key result
Direct renin inhibition ameliorated proteinuria (20.33 vs 83.64 mg/day) and markedly reduced glomerular crescent formation (20.9% vs 62.1%) in a rat model of anti-GBM nephritis.
Why the study?
The regulation and role of (pro)renin receptor in the pathogenesis of glomerulonephritis were poorly defined.
Absolute Event Rate: 20.9% vs 62.1%
Direct renin inhibition mitigates the progression of crescentic glomerulonephritis by reducing (P)RR expression, which regulates crescent formation via ERK1/2 and Wnt/β-catenin pathways.
Supports preclinical testing of direct renin inhibition for crescentic GN; leaves open clinical translation.
(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 the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent 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%), 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-glomerular basement membrane 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.
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Urushihara et al. (2020) studied Glomerulonephritis. Direct renin inhibition (DRI) vs. Untreated anti-glomerular basement membrane nephritis model was evaluated on Glomerular crescent formation. Direct renin inhibition ameliorated proteinuria (20.33 vs 83.64 mg/day) and markedly reduced glomerular crescent formation (20.9% vs 62.1%) in a rat model of anti-GBM nephritis.
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