H 2 S Therapy Improves MMP‐9 and NMDA Receptor Mediated Diabetic Renovascular Remodeling

Previously we reported that matrix metalloproteinase‐9 (MMP‐9) plays an important role in extracellular matrix (ECM) remodeling in diabetic kidney due to decreased H 2 S production by downregulation of CBS/CSE. Altered ECM resulted from NMDA‐R induction and dysregulation of connexins (Cxs). In this study, we determined whether H 2 S treatment reduces MMP‐9 induced ECM remodeling in diabetic nephropathy. Wild type (C57BL/6J), diabetic (Akita, C57BL/6J‐ Ins2 Akita ), 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 H 2 S treatment. DKO mice showed improved blood flow with H 2 S treatment. Akita and DKO mice showed low levels of CBS/CSE and thus H 2 S production. The levels of MMP‐9, NMDA‐R and Cxs‐40 and ‐43 were increased in Akita which normalized with H 2 S supplementation. DKO mice showed a decreasing trend for NMDA‐R and Cxs but the levels normalized only after H 2 S treatment. We conclude that H 2 S treatment reduces adverse diabetic renal remodeling by downregulation of MMP‐9 and NMDA‐R.