S8-5 Diabetic renal remodeling: Role of hydrogen sulfide

Abstract

Matrix mettaloproteinase-9 (MMP-9) and H2S has been shown to modulate pathogenesis of diabetic nephropathy. However, the regulation of these molecules and their cross-talk in diabetic kidney is still unclear. Using WT, diabetic (Akita), MMP-9 (-/-), double knockout (DKO) of Akita/MMP-9(-/-) mice, and in vitro cell culture we have previously reported that MMP-9-mediated H2S generation triggered renovascular remodeling in diabetes. In hyperglycemic mice increased oxidative stress, induction of MMP-9, alteration in microRNAs expressions, and diminished expressions of CBS and CSE with concomitant decreased production of H2S were measured. In addition, increased expressions of NMDA-R1 and connexins (Cxs)-40 and -43 were also observed in diabetic kidney. In DKO mice, all the above molecules showed a trend toward baseline despite hyperglycemia. In vitro, glomerular endothelial cells treated with high glucose showed induction of MMP-9, attenuated H2S production, NMDA-R1 induction, and dysregulated Cxs expressions. Silencing MMP-9 by siRNA or inhibition of NMDA-R1 by MK801 or H2S treatment preserved Cxs-40 and -43. Our ongoing studies have revealed that deregulation of poly-(ADP-ribose)-polymerase 1 (PARP1) in hyperglycemic condition enhanced extracellular matrix (ECM) synthesis resulting in accumulation of matrix proteins. Interestingly, H2S treatment mitigated matrix remodeling. Furthermore, H2S-mediated formation of STRAD/MO25/LKB1 tri-molecular complex [STE20-related protein (STRAD), mouse protein-25, and liver kinase B1 (LKB1)] led the activation of AMP-K (adenosine monophosphate-activated protein kinase), and modulated autophagy in hyperglycemia. Together, these results suggest that in diabetic renovascular remodeling MMP-9 plays a major role and that H2S mitigates adverse remodeling.