Metrnl Alleviates Lipid Accumulation by Modulating Mitochondrial Homeostasis in Diabetic Nephropathy

Abstract

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.

Serum Metrnl is Decreased in Metabolic Dysfunction-Associated Fatty Liver Disease: A Case-Control Study

“… 35 Considering the association of atherosclerosis and blood pressure, 36 the inverse correlation between Metrnl and blood pressure can be well explained. Zhou et al 37 reported that recombinant Metrnl administration or Metrnl-specific overexpression in the kidney relieves renal injuries in diabetic mice. Here we show serum Metrnl is inversely related to Creatinine, in line with previous result.…”

Lipid metabolism disorder in diabetic kidney disease

“…Metrnl is a recently discovered hormone produced by skeletal muscles and adipose tissue in response to exercise and cold exposure. Metrnl-specific overexpression or recombinant Metrnl administration in the kidney regulates renal tubular lipid metabolism through mitochondrial homeostasis mediated by the Sirtuin 3(Sirt3)-AMPK/uncoupling protein 1(UCP1) signaling axis, alleviates renal injury, and delays DKD in diabetic mice ( 193 ).…”

Redox signaling and skeletal muscle adaptation during aerobic exercise

“… 144 SIRT3 deacetylates mitochondrial uncoupling protein 1 (UCP1), promoting the dissipation of proton gradient across the inner mitochondrial membrane, which leads to the generation of heat instead of ATP. 145 , 146 Additionally, ROS can induce post-translational modifications to promote the activation of UCPs and subsequently trigger mitochondrial uncoupling. 147 Moreover, SIRT3 contributes to glutathione production by activating isocitrate dehydrogenase (IDH2), which catalyzes the oxidation of isocitrate to generate α-ketoglutarate and produce NAD(P)H. 148 Further, NADPH is crucial in reducing GSSG to GSH 149 and serves as an electronic transmitter for NOS or NOXs to generate NO or O 2 ·- /H 2 O 2 .…”