Accelerating Wound Closure With Metrnl in Normal and Diabetic Mouse Skin.

Impaired wound healing and ulcer complications are major causes of morbidity in patients with diabetes. Impaired wound healing is associated with increased inflammation and poor angiogenesis in diabetes patients. Here, we demonstrate that topical administration of a secreted recombinant protein (Meteorin-like [Metrnl]) accelerates wound epithelialization and angiogenesis in mice. We observed a significant increase in Metrnl expression during physiological wound healing; however, its expression remained low during diabetic wound healing. Functionally, the recombinant protein Metrnl significantly accelerated wound closure in normal and diabetic mice models including db/db, high-fat diet/streptozotocin (HFD/STZ), and STZ mice. Mechanistically, keratinocytes secrete quantities of Metrnl to promote angiogenesis; increase endothelial cell proliferation, migration, and tube formation; and enhance macrophage polarization to the M2 type. Meanwhile, M2 macrophages secrete Metrnl to further stimulate angiogenesis. Moreover, the keratinocyte- and macrophage-produced cytokine Metrnl drives postinjury angiogenesis and reepithelialization through activation of AKT phosphorylation (S473) in a KIT receptor tyrosine kinase (c-Kit)-dependent manner. In conclusion, our study suggests that Metrnl has a biological effect in accelerating wound closure through c-Kit-dependent angiogenesis and epithelialization.

Metrnl Alleviates Lipid Accumulation by Modulating Mitochondrial Homeostasis in Diabetic Nephropathy.

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.

The UDPase ENTPD5 regulates ER stress-associated renal injury by mediating protein N-glycosylation.

Impaired protein N-glycosylation leads to the endoplasmic reticulum (ER) stress, which triggers adaptive survival or maladaptive apoptosis in renal tubules in diabetic kidney disease (DKD). Therapeutic strategies targeting ER stress are promising for the treatment of DKD. Here, we report a previously unappreciated role played by ENTPD5 in alleviating renal injury by mediating ER stress. We found that ENTPD5 was highly expressed in normal renal tubules; however, ENTPD5 was dynamically expressed in the kidney and closely related to pathological DKD progression in both human patients and mouse models. Overexpression of ENTPD5 relieved ER stress in renal tubular cells, leading to compensatory cell proliferation that resulted in hypertrophy, while ENTPD5 knockdown aggravated ER stress to induce cell apoptosis, leading to renal tubular atrophy and interstitial fibrosis. Mechanistically, ENTPD5-regulated N-glycosylation of proteins in the ER to promote cell proliferation in the early stage of DKD, and continuous hyperglycemia activated the hexosamine biosynthesis pathway (HBP) to increase the level of UDP-GlcNAc, which driving a feedback mechanism that inhibited transcription factor SP1 activity to downregulate ENTPD5 expression in the late stage of DKD. This study was the first to demonstrate that ENTPD5 regulated renal tubule cell numbers through adaptive proliferation or apoptosis in the kidney by modulating the protein N-glycosylation rate in the ER, suggesting that ENTPD5 drives cell fate in response to metabolic stress and is a potential therapeutic target for renal diseases.