Abstract: Objective To investigate whether GYY4137, a sustained-release agent of hydrogen sulfide, plays a protective role in diabetic kidney disease and its possible mechanism.Methods C57BL/6J mice were injected with STZ (50 mg/kg×4 d) intraperitoneally and high-fat diet to induce a diabetes kidney disease (DKD) model. The modeled mice were divided into two groups:STZ+GYY 4137 group (H₂S group) administered intraperitoneally with 20 mg/kg GYY 4137, and STZ + physiological saline group (DKD group) administered intraperitoneally with the same amount of physiological saline. IN addition, normal C57BL/6J-1 mice were taken as the normal control group administered intraperitoneally with the same amount of physiological saline alone. After administering continuously for 12 weeks, 24-hour urinary albumin, renal histomorphological changes and apoptosis of renal tissue cells in all the groups were observed. Hydrogen sulfide probes were used to detect the site of hydrogen sulfide production, and immunohistochemistry was used to detect the distribution of hydrogen sulfide-producing enzymes in the kidney. The proximal tubular epithelial cells were stimulated by high D-glucose (25 mmol/L) and incubated with hydrogen sulfide to observe the apoptosis. Results 24-hour urinary albumin was increased in the DKD group compared with the control group, and hydrogen sulfide treatment reduced urinary albumin in DKD mice. The glomerular mesangial cells proliferated in the DKD group, glomerular mesangial proliferation in diabetic mice was improved by hydrogen sulfide; renal tissue apoptosis cell increased in DKD mice, while that was alleviate by hydrogen sulfide. Hydrogen sulfide was mainly produced in renal tubules. Hydrogen sulfide producing enzymes:cystathionine β synthase (CBS), cystathionine β-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MST) were all expressed in kidneys. CBS decreased in DKD mice, but CSE and MST did not change compared with normal mice. Cleaved-caspase 3 increased in proximal tubular epithelial cells stimulated by high glucose, and hydrogen sulfide pre-incubation decreased cleaved-caspase 3 expression and improved apoptosis.Conclusions Hydrogen sulfide treatment can reduce urinary albumin and mesangial proliferation in DKD mice, probably by reducing apoptosis of renal tubular epithelial cells induced by high glucose through decrease in caspase-3 activity.