title: 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 (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.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine Louisville, KY-40292.
authors.forename: Sathnur B
authors.initials: SB
authors.lastname: Pushpakumar
authors.forename: Sourav
authors.initials: S
authors.lastname: Kundu
authors.forename: Naira
authors.initials: N
authors.lastname: Metreveli
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
authors.forename: Utpal
authors.initials: U
authors.lastname: Sen
keywords: Dahl-salt sensitive; autophagy; collagen; extracellular matrix; fibrosis; vascular density