IL-37 Ameliorates Renal Fibrosis by Restoring CPT1A-Mediated Fatty Acid Oxidation in Diabetic Kidney Disease

• Published in: Kidney diseases 2023-04, Vol.9 (2), p.104-117
• Main Authors: Xiong, Li, He, Ting, Liu, Chi, Qin, Shaozong, Xiao, Tangli, Xin, Wang, Wang, Yaqin, Ran, Li, Zhang, Bo, Zhao, Jinghong
• Format: Article
• Language: English
• Subjects: Analysis; Carnitine; Chronic kidney failure; Fatty acids; Fibrosis; Genetic engineering; Health aspects; Interleukins; Oxidation-reduction reaction; Research Article
• ISSN: 2296-9381; 2296-9357
• DOI: 10.1159/000529460

Introduction: Diabetic kidney disease (DKD) is a major source of chronic kidney disease and end-stage renal disease. The injury of glomerulus in DKD is the primary focus; however, proximal tubulopathy also is an indispensable factor in the progression of DKD. Interleukin-37 (IL-37), an anti-inflammatory cytokine of IL-1 family member, has been demonstrated to be associated with diabetes and its relative complications in recent years, but the effect of IL-37 on renal fibrosis in DKD is unclear. Methods: We established streptozotocin plus high fat diet-induced DKD mice model with wild type or IL-37 transgenic mice. Masson and HE staining, immunostaining, and Western blot were used to observe renal fibrosis. In addition, RNA-sequencing was applied to explore the potential mechanisms of IL-37. In vitro, treatment of human proximal tubular (HK-2) cells with 30 mmol/L high glucose or 300 ng/mL recombinant IL-37 further elucidated the possible mechanism of IL-37 inhibition of DKD renal fibrosis. Results: In this work, we first verified the decreased expression of IL-37 in kidney of DKD patient and its correlation with clinical features of renal impairment. Moreover, IL-37 expression markedly attenuated proteinuria and renal fibrosis in DKD mice. Using RNA-sequencing, we found and confirmed a novel role of IL-37 in ameliorating fatty acid oxidation (FAO) reduction of renal tubular epithelial cells both in vivo and in intro. In addition, further mechanistic studies showed that IL-37 alleviated the FAO reduction in HK-2 cells and renal fibrosis in DKD mice through upregulating carnitine palmitoyl-transferase 1A (CPT1A), an important catalyzer for FAO pathway. Conclusion: These data suggest that IL-37 attenuates renal fibrosis via regulating FAO in renal epithelial cells. Upregulation of IL-37 levels might be an effective therapeutic avenue for DKD.