Abstract 347: The Role of Matrix Metalloproteinase-2 During the Development of Hypertension-induced Renal Injury in Dahl Salt-sensitive Rats.

Abstract

We recently reported that the progression of hypertension-induced renal injury in Dahl salt-sensitive (SS) rats was associated with increased renal expression of matrix metalloproteinase-2 (MMP-2) protein. Moreover, chronic treatment with a non-selective MMP inhibitor reversed the progression of renal injury in SS rats fed a high salt (HS) diet. In the present study, we created an 8 base pair frame-shift deletion in exon 7 of the MMP-2 gene within the genetic background of the SS rat (MMP-2 ZN KO strain) using Zinc-finger nucleases to study MMP-2 during the development of hypertension-induced renal injury in SS rats fed a HS diet containing 8.0% NaCl. MAP (measured by telemetry) rose from 112±3 to 166±10 mmHg in SS rats (n=6) fed a HS diet for 4 weeks. In contrast, MAP only increased to 140±4 mmHg in MMP-2 ZN KO rats (n=10). Proteinuria rose from 82±9 to 267±18 in SS rats fed a HS diet for 4 weeks vs. 24±2 to 139±11 mg/day in the MMP-2 ZN KO strain. MMP-2 protein and activity (measured by zymography) were significantly higher in the renal cortex of SS rats fed a HS diet when compared to the levels observed in SS rats on a low salt (LS) diet containing 0.3% NaCl. We detected very low levels of MMP-2 protein expression and activity in the renal cortex and glomeruli of MMP-2 ZN KO rats relative to that seen in SS rats fed either a LS or HS diet. The kidneys of SS rats fed a HS diet for 4 weeks exhibited severe glomeruloslcerosis and renal fibrosis and the degree of renal injury was markedly reduced in the MMP-2 ZN KO strain. These results indicate that upregulation of MMP-2 contributes to the development of hypertension-induced renal injury in SS rats fed a HS diet and suggest that specific MMP-2 inhibitors may be a new therapeutic target to slow the progression of chronic kidney disease in hypertensive and diabetic patients.