Activation of renal CSE/H2S pathway by alpha-lipoic acid protects against histological and functional changes in the diabetic kidney

Introduction: We previously reported that alpha-lipoic acid (ALA) supplementation protects against progression of diabetic kidney disease (DKD). In this study, we aim to investigate whether the mechanism of renal protection by ALA involves renal cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) system in type 2 diabetes mellitus (T2DM). Methods: Thirty-seven male Sprague-Dawley rats underwent 12 h of overnight fasting. To induce T2DM, 30 of these rats received intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). T2DM rats then received either oral administration of ALA (60 mg/kg/day) or intraperitoneal administration of 40 mg/kg/day DL-propargylglycine (PAG, a CSE inhibitor) or both for 6 weeks after which rats were sacrificed and samples collected for analysis. Untreated diabetic and non-diabetic rats served as diabetic and healthy controls respectively. Results: T2DM was characterized by reduced pancreatic beta-cell function and hyperglycemia. Histologically, un-treated diabetic rats showed significantly damaged pancreatic islets, glomerular and tubular injury, with elevated levels of renal function markers compared to healthy control rats (p < 0.001). These pathological changes worsened significantly following PAG administration (p < 0.05). While some renal protection was observed in ALA+PAG rats, ALA administration in untreated diabetic rats provided superior protection com-parable to healthy control rats, with improved antioxidant status, lipid profile and reduced inflammation. Mechanistically, ALA significantly activated renal CSE/H2S system in diabetic rats, which was markedly sup-pressed in PAG-treated rats (p < 0.001). Conclusion: Our data suggest that ALA protects against DKD development and progression by activating renal CSE/H2S pathway. Hence, CSE/H2S pathway may represent a therapeutic target in the treatment or prevention of DKD in diabetic patients.