Abstract
Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with metabolic disorders and chronic inflammation. Although the cytokine IL-22 was initially implicated in the pathogenesis of chronic inflammatory diseases, recent studies suggested that IL-22 could suppress inflammatory responses and alleviate tissue injury. Herein, we examined the role of IL-22 in DN. We found that serum levels of IL-22 were significantly downregulated in both patients and mice with DN. The expression of IL-22 was further decreased with the progression of DN, whereas IL-22 gene therapy significantly ameliorated renal injury and mesangial matrix expansion in mice with established nephropathy. IL-22 could also markedly reduce high glucose-induced and TGF-β1-induced overexpression of fibronectin and collagen IV in mouse renal glomerular mesangial cells in a dose-dependent manner, suggesting the potential role of IL-22 to inhibit the overproduction of ECM in vitro. Simultaneously, IL-22 gene therapy drastically alleviated renal fibrosis and proteinuria excretion in DN. In addition, IL-22 gene therapy markedly attenuated hyperglycemia and metabolic disorders in streptozotocin-induced experimental diabetic mice. Notably, IL-22 drastically reversed renal activation of NLRP3, cleavage of caspase-1, and the maturation of IL-1β in DN, suggesting unexpected anti-inflammatory function of IL-22 via suppressing the activation of NLRP3 inflammasome in vivo. Moreover, IL-22 markedly downregulated high glucose-induced activation of NLRP3 inflammasome in renal mesangial cells in a dose-dependent manner, indicating that the effects of IL-22 on NLRP3 inflammasome activation was independent of improved glycemic control. These results suggested that nephroprotection by IL-22 in DN was most likely associated with reduced activation of NLRP3 inflammasome. In conclusion, our finding demonstrated that IL-22 could exert favorable effects on DN via simultaneously alleviating systemic metabolic syndrome and downregulating renal NLRP3/caspase-1/IL-1β pathway, suggesting that IL-22 might have therapeutic potential for the treatment of DN.
Highlights
Diabetic nephropathy (DN), characterized clinically by progressive increase in proteinuria, and pathologically by excessive deposition of extracellular matrix (ECM) components, and subsequent glomerulosclerosis and tubulointerstitial fibrosis, is the leading cause of end-stage renal disease (ESRD) worldwide
On the basis of identifying the possible association between the downregulation of IL-22 and the progression of DN, we provided in vivo evidence for the first time that IL-22 significantly alleviated renal injury and fibrosis in established DN
We reported for the first time that IL-22 gene therapy suppressed the systemic pathogenesis of DN, including hyperglycemia and metabolic disorders, and protected against renal pathogenesis via suppression of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activation
Summary
Diabetic nephropathy (DN), characterized clinically by progressive increase in proteinuria, and pathologically by excessive deposition of extracellular matrix (ECM) components, and subsequent glomerulosclerosis and tubulointerstitial fibrosis, is the leading cause of end-stage renal disease (ESRD) worldwide. It has been generally recognized that the development and progression of DN are attributed to multiple interconnected mechanisms, including initial systemic pathogenesis such as hyperglycemia and metabolic disorders, as well as subsequent renal pathogenesis such as fibrosis and inflammation.[1,2,3,4] it is crucial to identify a novel therapy for DN that simultaneously improves the systemic pathogenesis and renal pathogenesis to protect against diabetic kidney complications.[5,6,7,8]. Activation of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is an important contributor to renal inflammation and fibrosis in chronic kidney disease via processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18.23–28 Notably, it Systems Biomedicine, Shanghai Jiao Tong University, School of Medicine, Shanghai 200240, China. Investigating the therapeutic effects and deciphering the underlying mechanisms of IL-22 could lead to the development of novel therapies for DN, providing scientific basis for therapeutic strategies for DKD on the basis of simultaneous regulation of metabolism and NLRP3 inflammasome activation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
