Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H₂S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H₂S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H₂S production by renal cells is reduced under disease states and H₂S donors ameliorate kidney injury. Specifically, aberrant H₂S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H₂S in diabetic renal disease and the underlying mechanisms for the protective effects of H₂S against diabetic renal damage. H₂S may serve as fundamental strategies to treat diabetic kidney disease. These H₂S treatment modalities include precursors for H₂S synthesis, H₂S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H₂S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H₂S in the kidney may be vital to translate H₂S to be a novel therapy for diabetic renal disease.

Vascular calcification can be enhanced by hyperglycemia. Elastin loss in tunica media promotes the osteogenic transformation of smooth muscle cells (SMCs) and involves arterial medial calcification (AMC) that is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes. Here, we tested whether hydrogen sulfide (H₂S), an endogenous gaseous mediator, can prevent elastin loss and attenuate calcification induced by high glucose in SMCs. Calcification was induced by high glucose (4500 mg/L) in human aortic SMCs (HASMCs) under the condition of calcifying medium containing 10 mM β-glycerophosphate (β-GP). The experiments showed that NaHS (an H₂S donor, 100 μM) mitigated the calcification of HASMCs treated with high glucose by decreasing calcium and phosphorus levels, calcium deposition and ALP activity and inhibited osteogenic transformation by increasing SMα-actin and SM22α, two phenotypic markers of smooth muscle cells, and decreasing core binding factor α-1 (Cbfα-1), a key factor in bone formation, protein expressions in HASMCs. Moreover, NaHS administration inhibited the activation of Stat3, cathepsin S (CAS) activity and its expression, but increased the level of elastin protein. Pharmacological inhibition or gene silencing Stat3 not only reversed elastin loss, but also attenuated CAS expression. Inhibition of CAS alleviated, while CAS overexpression exacerbated, elastin loss. Interestingly, overexpression of wild type (WT)-Stat3, but not its mutant C259S, elevated CAS protein expression and reduced elastin level. Moreover, NaHS induced S-sulfhydration in WT, but not in the C259S Stat3. These data suggest that H₂S may directly regulate Cys259 residue in Stat3 and then impair its signaling function. Our data indicate that H₂S may attenuate vascular calcification by upregulating elastin level through the inhibition of Stat3/CAS signaling.