Matrix metalloproteinase inhibition mitigates renovascular remodeling in salt‐sensitive hypertension. Issue 3 (22nd August 2013)

• Record Type: Journal Article
• Authors: Pushpakumar, Sathnur B.; Kundu, Sourav; Metreveli, Naira; Tyagi, Suresh C.; Sen, Utpal
• Is Part Of: Physiological reports. Volume 1:Issue 3(2013:Aug.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2013-08-22
• Subjects: Physiology -- Periodicals; 571
• DOI: 10.1002/phy2.63
• Languages: English
• ISSNs: 2051-817X

Abstract

<abstract abstract-type="main" id="phy263-abs-0001"> <title>Abstract</title> <p>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 intraperitoneal injection on alternate days for 4 weeks. Blood pressure (BP), renal cortical blood flow, vascular density, collagen, elastin, and MMPs/TIMPs were measured. GM6001 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 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 intrarenal 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.</p> </abstract>