Kaempferol improves mitochondrial homeostasis via mitochondrial dynamics and mitophagy in diabetic kidney disease

Abstract

Mitochondrial homeostasis imbalance plays an important role in the development of diabetic kidney disease (DKD). Kaempferol is a key bioactive compound widely present in the rhizomes of Kaempferia L. and vegetables. Its anti-inflammatory and antioxidant properties have gained increasing attention in treating various metabolic diseases. This study investigated whether kaempferol could improve mitochondrial structure and function by regulating mitochondrial dynamics and mitophagy in DKD. A DKD rat model was established via unilateral nephrectomy and streptozotocin injection. Renal function, histopathology, and inflammatory factors were assessed, along with fibrosis, apoptosis, mitochondrial dynamics, and mitophagy-related proteins. Meanwhile, an AGEs-induced HK-2 cell injury model was used to evaluate autophagic flux and mitochondrial function and morphology through ad-mCherry-GFP-LC3B transduction, JC-1 staining, and MitoTracker probes. In vivo results showed that kaempferol exhibited significant anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in DKD rats. Moreover, kaempferol demonstrated good safety by alleviating hepatic fibrosis. It also restored mitochondrial dynamics by promoting the upregulation of mitochondrial fusion proteins (Mfn1, OPA1) and the downregulation of fission proteins (Drp1, Fis1). In addition, kaempferol enhanced mitochondrial biogenesis by upregulating PGC-1α and TFAM. Notably, kaempferol reactivated mitophagy, as evidenced by increased levels of PINK1, Parkin, LC3, Beclin1, and ATG5, along with a reduction in p62 levels. In vitro, kaempferol further demonstrated its antioxidative potential by increasing SOD levels and decreasing MDA levels. Additionally, it promoted autophagic induction and facilitated the fusion of autophagosomes with lysosomes. These combined effects led to the restoration of mitochondrial membrane potential and structural integrity, while reducing ROS production and enhancing ATP generation. In conclusion, kaempferol promotes mitochondrial fusion, restores mitophagy, enhances autophagy flux, and facilitates mitochondrial clearance, showing the potential to mitigate kidney injury and slow disease progression in DKD.