Metrnl overexpression or recombinant Metrnl administration alleviated renal lipid accumulation and inhibited kidney failure in diabetic models via the Sirt3-AMPK/UCP1 signaling axis.
Does Metrnl administration or overexpression alleviate lipid accumulation and kidney failure in diabetic nephropathy models?
Metrnl regulates lipid metabolism in the kidney by modulating mitochondrial function, offering a potential novel therapeutic strategy for diabetic kidney disease.
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 a therapeutic strategy for the treatment of DKD. Here, we report that the 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 human 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 to promote thermogenesis, consequently alleviating lipid accumulation. In conclusion, our study demonstrates that Metrnl regulated lipid metabolism in the kidney by modulating mitochondrial function and is a stress-responsive regulator of kidney pathophysiology, which sheds light on novel strategies for treating DKD and associated kidney diseases. ARTICLE HIGHLIGHTS: Metrnl is expressed in renal tubules and is reduced under diabetic conditions. The concentration of Metrnl in the kidney is correlated with lipid accumulation and serum creatinine. Metrnl-specific overexpression in the kidney or recombinant Metrnl administration alleviates renal injuries in diabetic mice. Metrnl regulates renal tubules lipid metabolism through Sirt3-AMPK/UCP1 signaling axis-mediated mitochondrial homeostasis.
Zhou et al. (Wed,) conducted a other in Diabetic kidney disease (DKD). Metrnl overexpression or recombinant Metrnl vs. Control / Metrnl knockdown was evaluated on Lipid accumulation and kidney failure. Metrnl overexpression or recombinant Metrnl administration alleviated renal lipid accumulation and inhibited kidney failure in diabetic models via the Sirt3-AMPK/UCP1 signaling axis.