Matrix metalloproteinase 9 Contributes to Glomerulosclerosis by Causing Profibrotic Changes in Podocytes and Glomerular Endothelial Cells

Abstract

Background: Glomerulosclerosis is characterized by progressive (myo) fibroblast accumulation and collagen deposition involving profibrotic changes of podocytes and endothelial cells. A profibrotic role of MMP-9 in interstitial fibrosis has been reported. Whether MMP-9 plays a role in glomerulosclerosis is not clear yet. Methods: Mouse glomerulosclerosis model [Adriamycin Nephropathy (AN) model] was induced by a single adriamycin injection (10.2mg/kg, with physiological saline for controls) through tail vein in MMP-9-/- and wild-type control mice of BALB/c background. All animals were sacrificed at 4 weeks after injection. Albuminuria (albumin to creatinine ratio) and calculated GFR were measured. Gomori Trichrome (GT) and Sirius Red (SR) staining were used for assessment of glomerular fibrosis. Profibrotic changes of podocytes or glomerular endothelial cells were examined by confocal microscopy using immunofluorescence staining (IF) of desmin or a-SMA with P-cadherin or VEcadherin. Results: Albuminuria was reduced while GFR was increased in MMP-9-/- AN mice compared with those of wild-type mice. Confocal microscopy showed a significant decrease in podocytes double-stained with P-cadherin and desmin, demonstrating that MMP9-/- AN mice were protected from profibrotic changes in podocytes and glomerular endothelial cells. Glomerulosclerosis was significantly reduced in MMP9-/- AN mice compared to that of WT, as demonstrated by GT and SR staining. Conclusions: MMP-9 contributes to glomerulosclerosis at least in part by causing profibrotic changes in podocytes and glomerular endothelial cells.