Matrix metalloproteinase inhibition mitigates renovascular remodeling in salt‐sensitive hypertension

Abstract Extracellular matrix ( ECM ) remodeling is the hallmark of hypertensive nephropathy. Uncontrolled proteolytic activity due to an imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases ( MMP s/ TIMP s) has been implicated in renovascular fibrosis. We hypothesized that inhibition of MMP s will reduce excess ECM deposition and modulate autophagy to attenuate hypertension. Dahl salt‐sensitive (Dahl/ SS ) and Lewis rats were fed on high salt diet and treated without or with 1.2 mg/kg b.w. of GM 6001 ( MMP inhibitor) by intraperitoneal injection on alternate days for 4 weeks. Blood pressure (BP), renal cortical blood flow, vascular density, collagen, elastin, and MMP s/ TIMP s were measured. GM 6001 treatment significantly reduced mean BP in hypertensive Dahl/ SS rats. Renal resistive index ( RI ) was increased in hypertensive Dahl/ SS rats and Doppler flowmetry showed reduced cortical perfusion. Barium angiography demonstrated a reduction in terminal branches of renal vasculature. Inhibition of MMP s by GM 6001 resulted in a significant improvement in all the parameters including renal function. In hypertensive Dahl/ SS rats, protein levels of MMP ‐9, ‐2, and ‐13 were increased including the activity of MMP ‐9 and ‐2; TIMP ‐1 and ‐2 levels were increased whereas TIMP ‐3 levels were similar to Lewis controls. Administration of GM 6001 reduced the activity of MMP s and increased the levels of TIMP ‐1, ‐2, and ‐3. MMP inhibition reduced type 1 collagen deposition and increased elastin in the intrarenal vessels indicating reduced fibrosis. Autophagy markers were decreased in hypertensive Dahl/ SS rats and GM 6001 treatment enhanced their levels. We conclude that MMP inhibition ( GM 6001) reduces adverse renovascular remodeling in hypertension by modulating ECM turnover and stimulating autophagy.