Matrix metalloproteinase inhibition mitigates renovascular remodeling in salt-sensitive hypertension

Content Provider	Semantic Scholar
Author	Pushpakumar, Sathnur Basappa Kundu, Sourav Tyagi, Suresh C. Sen, Utpal
Copyright Year	2013
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.
Starting Page	488
Ending Page	493
Page Count	6
File Format	PDF HTM / HTML
PubMed reference number	24159376
Volume Number	1
Journal	Physiological reports
Language	English
Access Restriction	Open
Subject Keyword	Autophagy Barium Blood Vessel Blood supply aspects Collagen Extracellular Matrix Fibrosis GM 6001 Hypertensive disease Kidney Diseases Matrix Metalloproteinases Metalloproteases Sodium Chloride, Dietary Stimulation (motivation) Structure of cortex of kidney TIMP1 protein, human Tissue-Inhibitor of Metalloproteinase-1 angiogram antileukoprotease hypertensive nephropathy renovascular
Content Type	Text
Resource Type	Article