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.

中文翻译：

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Metrnl 通过调节糖尿病肾病线粒体稳态减轻脂质积累

肾小管中的异位脂质积累与糖尿病肾病 (DKD) 的发病机制密切相关，线粒体功能障碍被认为在脂质积累中起关键作用。因此，维持线粒体稳态作为治疗 DKD 的治疗策略具有相当大的前景。在这里，我们报道了镍纹蛋白样 (Metrnl) 基因产物介导肾脏中的脂质积累，并对 DKD 具有治疗潜力。我们证实了 Metrnl 在肾小管中的表达减少，这与患者和小鼠模型的 DKD 病理变化呈负相关。在功能上，重组 Metrnl (rMetrnl) 或 Metrnl 过表达的药理学给药可以减轻脂质积累并抑制肾衰竭。体外，rMetrnl 或 Metrnl 过表达减弱了棕榈酸诱导的线粒体功能障碍和肾小管中的脂质积累，同时维持了线粒体稳态并增加了脂质消耗。相反，shRNA 介导的 Metrnl 敲低削弱了对肾脏的保护作用。从机制上讲，Metrnl 的这些有益作用是由 Sirt3-AMPK 信号轴介导的，以维持线粒体稳态，并通过 Sirt3-解偶联蛋白-1 (UCP1) 促进产热，从而减轻脂质积累。总之，我们的研究表明，Metrnl 通过调节线粒体功能来调节肾脏中的脂质代谢，并作为肾脏病理生理学的应激反应调节剂，这为治疗 DKD 和相关肾脏疾病的新策略提供了思路。