Matrix metalloproteinase (MMP)-10 aggravates podocyte injury in glomerulonephritis

Abstract

Background: Podocytes are integral to maintaining glomerular filtration barrier. Our previous research underscored the crucial role of podocyte guanylyl cyclase-A (GC-A) in the pathogenesis of severe albuminuria in both systemic and podocyte-specific GC-A knockout mice subjected to heminephrectomy, high salt, and aldosterone (ALDO) treatment. This study investigates the role of matrix metalloproteinase-10 (MMP-10) on glomerular injury, which was found to be highly expressed in glomeruli of ALDO-treated GC-A knockout mice.

Methods: To investigate the role of MMP-10 in glomerulonephritis, we used MMP-10 knockout mice subjected to anti-glomerular basement membrane (GBM) nephritis. Additionally, we created systemic GC-A and MMP-10 double knockout mice, as well as podocyte-specific GC-A and systemic MMP-10 double knockout mice, to analyze glomerular injury. In vitro, changes in inflammatory mRNA are examined in MMP-10-overexpressing or -knockdown mouse podocytes following stimulation of tumor necrosis factor (TNF)-α.

Results: We demonstrate that MMP-10 is highly expressed in the kidneys of patients with glomerulonephritis. MMP-10 knockout mice showed less albuminuria and lower expression of pro-inflammatory and pro-fibrotic mRNAs compared to control mice in anti-GBM nephritis. Additionally, systemic or podocyte-specific GC-A and systemic MMP-10 knockout mice exhibited improved albuminuria, preserved nephrin expression, and reduced GBM thickening compared to systemic or podocyte-specific GC-A knockout mice with ALDO treatment. MMP-10 was co-localized with podocytes and endothelial cells. In vitro studies using mouse podocytes revealed that MMP-10 overexpression upregulated inflammatory mRNA changes induced by TNF-α, whereas MMP-10 knockdown mitigated inflammation. Co-culture of mouse podocytes with human endothelial cells showed reduced inflammation following MMP-10 reduction in endothelial cells. Moreover, activated MMP-10 cleaved nephrin in vitro, contributing to podocyte injury.

Conclusion: These findings suggest that GC-A ablation leads to upregulation of MMP-10, resulting in nephrin loss, and that systemic deletion of MMP-10 ameliorates GC-A-induced podocyte injury.

Keywords: aldosterone; anti-GBM glomerulonephritis; endothelial cells; natriuretic peptides.