Exercise training ameliorates early diabetic kidney injury by regulating the H₂S/SIRT1/p53 pathway

Abstract

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 (H2S) 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, H2S and diabetes + H2S groups. H2S 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 H2S 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 H2S production in renal tissues, thereby contributing to the modulation of the SIRT1/p53 apoptosis pathway and improvement of diabetic nephropathy.

The effect of two types of diet on apoptosis indexes, lipid profile and histopathological outcome in acute kidney injury during exercise

“…Better physical condition of exercised animals may lead to better hemodynamic and metabolic conditions and ultimately activation of molecular mechanisms of cell survival in kidney tissue [ 49 ]. SIRT1 expression was reduced in the AKI model [ 1 ], and it was shown that exercise reduces apoptosis by increasing SIRT1 expression [ 50 ]. SIRT1 is an evolutionary biological stress response that is associated with increased long-term function and survival of vital cell types [ 51 ].…”

Bibliometric Study of Trends in the Diabetic Nephropathy Research Space from 2016 to 2020

“…Moreover, there is evidence that exosomes and associated miRNAs can impact renal tissues either directly or in synergy with other factors to shape the development and progression of DN [ 37 , 38 ]. Signal transduction pathways and associated regulatory networks are important areas of DN-related research that offer important insight into the etiological basis for this debilitating condition [ 39 – 41 ]. The development of drugs targeting DN-related signal transduction pathways may also hold great promise as an area for future research [ 42 , 43 ].…”

The Nicotinamide/Streptozotocin Rodent Model of Type 2 Diabetes: Renal Pathophysiology and Redox Imbalance Features

“…Finally, this NA-STZ diabetes animal model may also be used to evaluate any potential renoprotective effects of caloric restriction [ 142 , 143 , 144 ], intermittent caloric restriction [ 145 , 146 ], exercise [ 147 , 148 , 149 , 150 ], and ketone bodies [ 151 , 152 , 153 , 154 ], which all have been demonstrated to provide beneficial effects on the kidney in a variety of pathological conditions [ 155 , 156 ]. Indeed, the underlying mechanisms of renoprotection conferred by these approaches in this non-obese type 2 diabetes model remain to be comprehensively elucidated.…”