Abstract
BACKGROUND: Recent investigations across both animal models and human cohorts increasingly highlight cellular senescence as a critical pathological process driving the development and progression of diabetic nephropathy (DN). The detrimental impact of senescent cells on DN advancement stems from a range of underlying mechanisms, notably telomere attrition, compromised mitochondrial function, dysregulated autophagy, chronic inflammatory responses, altered mTOR signaling and Sirtuin activity, and the release of pro-coagulant factors. Diabetic kidney disease (DKD) is a common and serious complication in diabetic patients, closely associated with high glucose-induced defects in kidney cells. Currently the clinical treatment of DKD disease is still a challenge. Celastrol, a compound derived from Tripterygium wilfordii, has shown significant therapeutic effects on DKD, but the specific mechanisms remain unclear. METHODS: We established in vitro and in vivo models of DKD using human renal tubular epithelial cells (HK-2) and Sprague-Dawley (SD) rats. The effects of celastrol on glucose-induced oxidative damage to HK-2 cells and kidney injury in DKD rats were observed. The potential mechanisms were investigated through both in vitro and in vivo experiments. RESULTS: High glucose induced accelerated senescence of HK-2 cells in vitro, and celastrol reversed senescence-associated pathological changes in the cells. Celastrol reduced pro-inflammatory signaling and mitochondrial damage in vitro by inhibiting the phosphorylation of aging- and inflammation-related proteins NF-κB and AKT1. In vivo, celastrol inhibited the phosphorylation of NF-κB and AKT1 in renal tissues, effectively improving renal dysfunction and pathological changes in DKD rats, and reducing disease-related indicators. CONCLUSION: Celastrol may be a promising candidate drug for the treatment of DKD. It can treat DKD by reversing the imbalance of the immune-inflammatory system mediated by the AKT/NF-κB/TNF-α signaling during the progression of the disease and may also delay the progression of DKD through its anti-aging effect.