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

Area of Science:

• Nephrology
• Biochemistry
• Physiology

Background:

• Diabetic kidney disease involves extracellular matrix (ECM) remodeling, mediated by matrix metalloproteinase-9 (MMP-9).
• Reduced hydrogen sulfide (H2S) production, due to decreased cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) enzyme activity, is implicated in diabetic kidney dysfunction.
• The protective role of H2S against MMP-9-induced ECM dysregulation and renal impairment in diabetes remains unclear.

Purpose of the Study:

• To investigate whether H2S supplementation can ameliorate MMP-9-induced ECM remodeling and renal dysfunction in a mouse model of diabetes.
• To elucidate the potential mechanisms involving MMP-9 and N-methyl-D-aspartate receptor 1 (NMDA-R1) in H2S-mediated renal protection.

Main Methods:

• Utilized wild-type, diabetic (Akita), MMP-9 knockout (MMP-9(-/-)), and double knockout (Akita/MMP-9(-/-)) mice.
• Administered sodium hydrosulfide (NaHS), a source of H2S, in drinking water to diabetic mice for 30 days.
• Assessed H2S levels, expression of MMP-9, CBS, CSE, NMDA-R1, connexins (Cxs), renal vascular parameters, and plasma creatinine.

Main Results:

• H2S supplementation normalized decreased H2S levels in diabetic Akita mice.
• H2S treatment restored dysregulated expression of MMP-9, CBS, CSE, NMDA-R1, and Cxs-40, -43 in Akita mice.
• Renal dysfunction markers, including renovascular resistive index, ECM deposition, plasma creatinine, renal vascular density, and cortical blood flow, were improved by H2S therapy in Akita mice.

Conclusions:

• Diminished H2S production in diabetic kidneys contributes to adverse renal remodeling.
• H2S therapy offers a potential therapeutic strategy for diabetic kidney disease.
• H2S improves renal function in diabetes via pathways involving MMP-9 and NMDA-R1.