Hydrogen sulfide inhibits high glucose-induced NADPH oxidase 4 expression and matrix increase by recruiting inducible nitric oxide synthase in kidney proximal tubular epithelial cells

Abstract

High-glucose increases NADPH oxidase 4 (NOX4) expression, reactive oxygen species generation, and matrix protein synthesis by inhibiting AMP-activated protein kinase (AMPK) in renal cells. Because hydrogen sulfide (HS) inhibits high glucose-induced matrix protein increase by activating AMPK in renal cells, we examined whether HS inhibits high glucose-induced expression of NOX4 and matrix protein and whether HS and NO pathways are integrated. High glucose increased NOX4 expression and activity at 24 h in renal proximal tubular epithelial cells, which was inhibited by sodium hydrosulfide (NaHS), a source of HS. High glucose decreased AMPK phosphorylation and activity, which was restored by NaHS. Compound C, an AMPK inhibitor, prevented NaHS inhibition of high glucose-induced NOX4 expression. NaHS inhibition of high glucose-induced NOX4 expression was abrogated by (ω)-nitro-l-arginine methyl ester, an inhibitor of NOS. NaHS unexpectedly augmented the expression of inducible NOS (iNOS) but not endothelial NOS. iNOS siRNA and 1400W, a selective iNOS inhibitor, abolished the ameliorative effects of NaHS on high glucose-induced NOX4 expression, reactive oxygen species generation, and, matrix laminin expression. Thus, HS recruits iNOS to generate NO to inhibit high glucose-induced NOX4 expression, oxidative stress, and matrix protein accumulation in renal epithelial cells; the two gasotransmitters HS and NO and their interaction may serve as therapeutic targets in diabetic kidney disease.

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

“…Resveratrol treatment in db/db mice prevented NOX4 expression primarily due to increased AMPK activity [132]. Similarly, numerous recent studies highlighted the beneficial effects of antioxidants or other compounds against renal injuries implicating AMPK/NOX4/ROS [133][134][135][136][137][138][139]. Furthermore, two independent studies reported that Sestrin-2 mediated activation of AMPK inhibits ROS production, podocyte impairment in the hyperglycemic condition, and suppresses NOX4 in glomerular mesangial cells [140,141].…”

Hydrogen Sulfide: Recent Progression and Perspectives for the Treatment of Diabetic Nephropathy

“…Moreover, the diabetic patients with dialysis exhibit reduced level of plasma H 2 S, and lower H 2 S level may contribute to uremic atherosclerosis in chronic hemodialysis patients with diabetic nephropathy [48]. Recent documents have demonstrated that renal H 2 S-producing enzymes CBS and CSE are downregulated in animals with type 1 or type 2 diabetes [45,49,50]. The above evidence indicates that H 2 S deficiency contributes to the development of diabetic kidney injury.…”

Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review

“…Fakhruddin et al in 2017 affirmed that in a hyperglycemic state, NOX enzymes are activated directly or by way of impeding adenosine monophosphate-(AMP-) activated protein kinase [88]. Furthermore, in a hyperglycemic state, there is enhancement of NOX4 expression and oxidant production in the kidney [151], while Eid et al [152] and Lee et al [153] showed that in the same state, there is a subduing effect on AMPactivated protein kinase, thus bringing about the upregulation of NOX4 and ultimately promoting NOX activity in the glomerulus.…”