Knockout of Matrix Metalloproteinase 2 Opposes Hypertension- and Diabetes-Induced Nephropathy

Abstract The progression of chronic kidney disease (CKD) results from the accumulation of extracellular matrix leading to end-stage renal disease. We previously demonstrated that a broad-spectrum metalloproteinase (MMP) inhibitor reduced renal injury in rat models of hypertension and diabetes. However, the isoforms and mechanisms involved are unclear. This study examined the role of MMP2 during the development of proteinuria and renal injury following induction of hypertension or diabetes in Dahl salt-sensitive (SS) and SS MMP2 knockout (KO) rats. Mean arterial pressure (MAP) rose from 115 ± 2 to 145 ± 2 mmHg and 116 ± 1 to 152 ± 3 mmHg in MMP2 KO and SS rats fed a high salt (HS; 8% NaCl) diet for 3 weeks. The degree of proteinuria, glomerular injury, renal fibrosis, and podocyte loss was lower in MMP2 KO than in SS rats. Blood glucose and HbA1c levels, and MAP rose to the same extent in streptozotocin (STZ)-treated SS and MMP2 KO rats. However, the degree of proteinuria, glomerulosclerosis, renal fibrosis, renal hypertrophy, glomerular permeability to albumin and the renal expression of MMP2 and TGFβ1 were significantly reduced in MMP2 KO rats. Glomerular filtration rate (GFR) fell by 33% after 12 weeks of diabetes in STZ-treated SS rats compared to time-control rats, but GFR only fell by 12% in MMP2 KO rats. These results indicate that activation of MMP2 plays an essential role in the pathogenesis of hypertensive and diabetic nephropathy and suggests that an MMP2 inhibitor might slow the progression of CKD.