Lipid nephrotoxicity mediated by HIF-1α activation accelerates tubular injury in diabetic nephropathy

Abstract

This study is intended to explore the effect of hypoxia-inducible factor-1α (HIF-1α) activation on lipid accumulation in the diabetic kidney. A type 1 diabetic rat model was established by STZ intraperitoneal injection. Cobalt chloride (CoCl₂) and YC-1 were used as the HIF-1α activator and antagonist, respectively. CoCl₂ treatment significantly increased HIF-1α expression, accelerated lipid deposition, and accelerated tubular injury in diabetic kidneys. In vitro, CoCl₂ effectively stabilized HIF-1α and increased its transportation from the cytoplasm to the nucleus, which was accompanied by significantly increased lipid accumulation in HK-2 cells. Furthermore, results obtained in vivo showed that HIF-1α protein expression in the renal tubules of diabetic rats was significantly downregulated by YC-1 treatment. Meanwhile, lipid accumulation in the tubules of the DM + YC-1 group was markedly decreased in comparison to the DM + DMSO group. Accordingly, PAS staining revealed that the pathological injury caused to the tubular epithelial cells was alleviated by YC-1 treatment. Furthermore, the blood glucose level, urine albumin creatinine ratio, and NAG creatinine ratio in the DM + YC-1 group were significantly decreased compared to the DM + DMSO group. Moreover, the protein expression levels of transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) in diabetic kidneys were decreased by YC-1 treatment. Our findings demonstrate that the activation of HIF-1α contributed to interstitial injury in a rat model of diabetic nephropathy and that the underlying mechanism involved the induction of lipid accumulation.

Keywords:

• Diabetic nephropathy
• HIF-1α
• YC-1
• lipid accumulation
• tubules
• HK-2

Author contributions

Ze-bo Hu designed the work, performed the research, conducted the data analysis, and wrote the manuscript. Qian-wen Zhu, Ying Wang, Xue Deng and Ming-jun Zhou assisted in cell culture. Hui Yang, Ji-yuan Zhang, Hao Wang, and Hao-sen Wang assisted in conducting the animal experiments. Lin Wang, Cui Zhang, and Shu Li contributed reagents and conducted manuscript polishing.

Disclosure statement

The authors declare no conflicts of interest.

Data availability statement

All data used and analyzed during this study will be available from the corresponding author upon reasonable request.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China Youth Fund under Grant 82000698; the Wuhu City Basic Research on the Application of Science and Technology Projects under Grant 2022jc28; the Wannan Medical College Doctoral Research Initiation Fund under Grant WYRCQD2019007; and the Wannan Medical College Student Research Funding Project under Grant WK2022XS53.