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 (
MMPs/TIMPs) has been implicated in renovascular
fibrosis. We hypothesized that inhibition of
MMPs 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
GM6001 (
MMP inhibitor) by intra-peritoneal injection on alternate days for 4 weeks. Blood pressure, renal cortical blood flow, vascular density,
collagen,
elastin and
MMPs/TIMPs were measured.
GM6001 treatment significantly reduced mean blood pressure in hypertensive Dahl/SS rats. Renal resistive index 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
MMPs by
GM6001 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
GM6001 reduced the activity of
MMPs and increased the levels of
TIMP-1, -2 and -3.
MMP inhibition reduced
type -1 collagen deposition and increased
elastin in the intra-renal vessels indicating reduced
fibrosis. Autophagy markers were decreased in hypertensive Dahl/SS rats and
GM6001 treatment enhanced their levels. We conclude that
MMP inhibition (
GM6001) reduces adverse renovascular remodeling in
hypertension by modulating ECM turnover and stimulating autophagy.