MMP-9- and NMDA receptor-mediated mechanism of diabetic renovascular remodeling and kidney dysfunction: Hydrogen sulfide is a key modulator

Abstract

Previously we reported that matrix metalloproteinase-9 (MMP-9) plays an important role in extracellular matrix (ECM) remodeling in diabetic kidney. Induction of NMDA-R and dysregulation of connexins (Cxs) were also observed. We concluded that this was due to decreased H2S production by down regulation of CBS and CSE enzymes. However, the potential role of H2S to mitigate ECM dysregulation and renal dysfunction was not clearly understood. The present study was undertaken to determine whether H2S supplementation reduces MMP-9-induced ECM remodeling and dysfunction in diabetic kidney. 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 (as a source of H2S) in drinking water for 30 days. Decreased tissue production and plasma content of H2S in Akita mice were ameliorated with H2S supplementation. Dysregulated expression of MMP-9, CBS, CSE, NMDA-R1 and Cxs-40, -43 were also normalized in Akita mice treated with H2S. In addition, increased renovascular resistive index (RI), ECM deposition, plasma creatinine, and diminished renal vascular density and cortical blood flow in Akita mice were normalized with H2S treatment. We conclude that diminished H2S production in renal tissue and plasma levels in diabetes mediates adverse renal remodeling, and H2S therapy improves renal function through MMP-9- and NMDA-R1-mediated pathway.

Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension

“…H 2 S was able to alleviate diabetic nephropathy in part by attenuating matrix deposition and inflammation [180]. Similar to their study, we also reported that in genetic diabetic Akita mice, diminished tissue and plasma H 2 S content was associated with matrix deterioration and diminished renal function [56, 57]. Increased matrix metalloproteinse-9 (MMP-9) expression and activity was noticed in Akita diabetic kidney which was normalized by H 2 S supplementation.…”

“…Direct correlation of diminished H 2 S and increased Ang-II was established by the fact that H 2 S treatment partially normalized all the above three effectors / inducers of hypertension in diabetic kidney [180]. Although this study in particular did not measure proteinuria and kidney function per se, we reported improved kidney function in Akita kidney [57]. Another study reported diuretic effect of H 2 S in spontaneously hypertensive diabetic rats in addition to reduction of blood pressure, restoration of H 2 S and plasma sodium levels compared to non-H 2 S treated diabetic rats [182].…”

“…The importance of insulin resistance, ROS, inflammation, dyslipidemia and many other factors are proposed in contributing MetS associated CKD; however, the role of H 2 S in this disease mechanism is poorly addressed. We have recently shown that in diabetes, H 2 S deficiency contributes to unfavorable renovascular remodeling characterized by vascular constriction, increased resistive index, and diminished blood flow, and H 2 S treatment improves renal function [56, 57]. Others have shown inhibition of pancreatic H 2 S production with daily intraperitoneal injections of CSE inhibitor dl -propargylglycine (PAG) in Zucker diabetic fatty (ZDF) rats increased serum insulin levels and reduced hyperglycemia [58].…”

“…Finally, we concluded that renovascular remodeling and dysfunction in Akita kidney was in part due to oxidative stress-mediated MMP-9 activation leading to imbalance in gap junction molecules and renal functional impairment. H 2 S treatments attenuated oxidative stress and MMP-9 activity, and therefore ameliorated kidney ECM remodeling and function in Akita [56, 57]. …”

Hydrogen Sulfide in Renal Physiology and Disease

“…In established diabetic kidney injury in the Akita mice with type 1 genetic diabetes, Kundu et al have employed multiple mutually confirmatory approaches, including renal resistive index, to show a decrease in renal cortical blood flow that was associated with reduced vascular density; these changes were improved by the administration of NaHS (46).…”