SIRT1-PINK1-Parkin axis orchestrated mitophagy and renal repair by dapagliflozin in diabetic nephropathy

Oct 17, 2025Biochimica et biophysica acta. Molecular basis of disease

How dapagliflozin may help kidney repair in diabetic kidney disease by controlling cell cleanup through the SIRT1-PINK1-Parkin pathway

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Abstract

Dapagliflozin significantly protected against streptozotocin-induced diabetic nephropathy.

Dapagliflozin restored mitochondrial membrane potential and reduced reactive oxygen species in high glucose-induced kidney cells.
High glucose exposure increased the expression of proteins linked to cell death, which was decreased by dapagliflozin treatment.
Mitophagy, a process for clearing damaged mitochondria, was found to be suppressed in diabetic conditions but activated by dapagliflozin.
The study highlights the role of the Sirt1-Pink1-Parkin pathway in mitochondrial health, which may be a target for therapeutic strategies in diabetic nephropathy.

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BACKGROUND: Mitochondrial dysfunction caused by metabolic stress is a key part of diabetic nephropathy. Dapagliflozin exerts significant hypoglycemic and nephroprotective effects; however, the precise mechanisms underlying its renoprotective actions remain to be fully elucidated.

OBJECTIVE: This study aimed to elucidate the molecular mechanisms through which dapagliflozin mitigates diabetic nephropathy (DN), with particular emphasis on its regulatory role in the Sirt1-Pink1-Parkin axis and the restoration of mitochondrial homeostasis via mitophagy.

METHODS: Rats were fed a high-fat/high-sugar diet and streptozotocin. They were then divided into groups of various treatments. In vitro, high glucose-induced NRK-52E cell injury was treated with dapagliflozin. Evaluations included renal histopathology, urinary biomarkers, apoptosis, reactive oxygen species, mitochondrial membrane potential, and Sirt1/Pink1/Parkin pathway activation.

RESULTS: Dapagliflozin exerted significant protective effects against streptozotocin-induced diabetic nephropathy. Dapagliflozin treatment in vitro restored mitochondrial membrane potential and reduced ROS levels in high glucose-induced NRK-52E cells. High glucose exposure markedly upregulated the expression of mitochondria-associated apoptotic proteins in NRK-52E cells, which was reduced by dapagliflozin. This study revealed that Sirt1/Pink1/Parkin-mediated mitophagy was suppressed in DN and high glucose-induced NRK-52E cells but was activated following dapagliflozin treatment.

CONCLUSION: Our findings demonstrate that dapagliflozin modulates Sirt1/Pink1/Parkin-mediated mitochondrial autophagy and effectively restores mitochondrial homeostasis in diabetic nephropathy. Modulating mitochondrial autophagy through this pathway may serve as a promising therapeutic strategy for diabetic nephropathy.

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SIRT1-PINK1-Parkin axis orchestrated mitophagy and renal repair by dapagliflozin in diabetic nephropathy

Abstract

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