Exercise training exerts protective effects against
diabetic nephropathy. This study aimed to investigate whether exercise training could attenuate diabetic renal injury via regulating endogenous
hydrogen sulfide (H2 S) production. First, C57BL/6 mice were allocated into the control, diabetes, exercise, and diabetes + exercise groups. Diabetes was induced by
intraperitoneal injection of
streptozotocin (STZ). Treadmill exercise continued for four weeks. Second, mice was allocated into the control, diabetes, H2 S and diabetes + H2 S groups. H2 S donor
sodium hydrosulfide (
NaHS) was intraperitoneally injected once daily for four weeks. STZ-induced diabetic mice exhibited glomerular
hypertrophy, tissue
fibrosis and increased urine
albumin levels, urine
protein- and
albumin-to-
creatinine ratios, which were relieved by exercise training. Diabetic renal injury was associated with apoptotic cell death, as evidenced by the enhanced
caspase-3 activity, the increased TdT-mediated dUTP nick-end labeling -positive cells and the reduced expression of
anti-apoptotic proteins, all of which were attenuated by exercise training. Exercise training enhanced renal
sirtuin 1 (
SIRT1) expression in diabetic mice, accompanied by an inhibition of the p53-#ediated pro-apoptotic pathway. Furthermore, exercise training restored the STZ-mediated downregulation of
cystathionine-β-synthase (CBS) and
cystathionine-γ-
lyase (CSE) and the reduced renal H2 S production.
NaHS treatment restored
SIRT1 expression, inhibited the p53-mediated pro-apoptotic pathway and attenuated diabetes-associated apoptosis and renal injury. In high
glucose-treated
MPC5 podocytes,
NaHS treatment inhibited the p53-mediated pro-apoptotic pathway and podocyte apoptosis in a SIRT1-dependent manner. Collectively, exercise training upregulated CBS/CSE expression and enhanced the endogenous H2 S production in renal tissues, thereby contributing to the modulation of the
SIRT1/p53 apoptosis pathway and improvement of
diabetic nephropathy.