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Matrix Metalloproteinase Inhibition Protects Kidney from Adverse Remodeling Induced by Hypertension
Author(s) -
Pushpakumar Sathnur,
Kundu Sourav,
Metreveli Naira,
Tyagi Suresh C,
Sen Utpal
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.906.6
Subject(s) - matrix metalloproteinase , medicine , endocrinology , elastin , fibrosis , kidney , autophagy , extracellular matrix , chemistry , pathology , biochemistry , apoptosis
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 renal 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 fed on high salt diet were treated without or with 0.5mg/mL of GM6001 (MMP inhibitor) by intra‐peritoneal injection on alternate days for 3 weeks. GM6001 treatment significantly reduced mean blood pressure in Dahl‐SS rats compared to its untreated controls. Renal ultrasound revealed increased resistive index in Dahl‐SS controls indicating vascular stiffness which improved upon treatment. Barium angiography demonstrated a reduction in terminal branches of renal vessels in Dahl‐SS controls and GM6001 treatment resulted in significant improvement. MMP inhibition reduced type‐1 collagen and increased elastin in renal vessels indicating reduced fibrosis. Untreated Dahl‐SS rats exhibited high levels of superoxide anion and decreased levels of autophagy which was mitigated by GM6001 treatment. We conclude that MMP inhibition (GM6001) reduces adverse renal remodeling in hypertension by decreasing ECM turnover and stimulating autophagy.