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Metrnl alleviates lipid accumulation by modulating mitochondrial homeostasis in diabetic nephropathy

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posted on 2023-02-22, 22:10 authored by Yuxia Zhou, Lu Liu, Bangming Jin, Yixuan Wu, Lifen Xu, Xuebing Chang, Laying Hu, Guifang Wang, Yali Huang, Lingyu Song, Tian Zhang, Yuanyuan Wang, Ying Xiao, Fan Zhang, Mingjun Shi, Lingling Liu, Tuanlao Wang, Rui Yan, Bing Guo

Ectopic lipid accumulation in renal tubules is closely related to the pathogenesis of diabetic kidney disease (DKD) and mitochondrial dysfunction is thought to play a key role in lipid accumulation. Therefore, maintaining mitochondrial homeostasis holds considerable promise as therapeutic strategies for the treatment of DKD. Here we reported that Meteorin-like (Metrnl) gene product mediates lipid accumulation in the kidney and has therapeutic potential for DKD. We confirmed the reduced expression of Metrnl in renal tubules, which was inversely correlated with DKD pathological changes in patients and mouse models. Functionally, pharmacological administration of recombinant Metrnl (rMetrnl) or Metrnl overexpression could alleviate lipid accumulation and inhibit kidney failure. In vitro, rMetrnl or Metrnl overexpression attenuated palmitic acid-induced mitochondrial dysfunction and lipid accumulation in renal tubules accompanied by maintained mitochondrial homeostasis and enhanced lipid consumption. Conversely, shRNA-mediated Metrnl knockdown diminished the protective effect on the kidney. Mechanistically, these beneficial effects of Metrnl were mediated by the Sirt3-AMPK signaling axis to maintain mitochondrial homeostasis, and through Sirt3-uncoupling protein-1(UCP1) to promote thermogenesis, consequently alleviating lipid accumulation. In conclusion, our study demonstrated that Metrnl regulated lipid metabolism in the kidney by modulating mitochondrial function and serves as a stress-responsive regulator of kidney pathophysiology, which sheds light on novel strategies for treating DKD and associated kidney diseases. 


This study was supported by National Natural Science Foundation of China (No. 82000741, 32160207, 82170743, 82060111 and 8200299). China Postdoctoral Science Foundation (2020M683374), Guizhou Provincial Science and Technology Projects (ZK [2021]402), and Universities Young Science and Technology Talent Growth Project in Guizhou Province (KY [2021]170). Excellent Young Talents Plan of Guizhou Medical University (2021105).