Abstract
Previously we reported that matrix metalloproteinase‐9 (MMP‐9) plays an important role in extracellular matrix (ECM) remodeling in diabetic kidney due to decreased H2S production by downregulation of CBS/CSE. Altered ECM resulted from NMDA‐R induction and dysregulation of connexins (Cxs). In this study, we determined whether H2S treatment reduces MMP‐9 induced ECM remodeling in diabetic nephropathy. Wild type (C57BL/6J), diabetic (Akita, C57BL/6J‐Ins2Akita), MMP‐9 knockout (MMP‐9−/−, M9KO) and double KO of Akita/MMP‐9−/− (DKO) mice were treated without or with 0.05 g/L of NaHS in drinking water. Cortex blood flow, renal function, vascularity, MMP‐9, NMDA‐R, Cxs, collagen and elastin were measured. Diabetic mice showed decreased cortical blood flow and vascularity which improved with H2S treatment. DKO mice showed improved blood flow with H2S treatment. Akita and DKO mice showed low levels of CBS/CSE and thus H2S production. The levels of MMP‐9, NMDA‐R and Cxs‐40 and ‐43 were increased in Akita which normalized with H2S supplementation. DKO mice showed a decreasing trend for NMDA‐R and Cxs but the levels normalized only after H2S treatment. We conclude that H2S treatment reduces adverse diabetic renal remodeling by downregulation of MMP‐9 and NMDA‐R.
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