IL-17 deficiency aggravates the streptozotocin‐induced diabetic nephropathy through the reduction of autophagosome formation in mice

Abstract

Background Diabetic nephropathy (DN) is one of the most important medical complications of diabetes mellitus. Autophagy is an important mediator of pathological response and plays a critical role in inflammation during the progression of diabetic nephropathy. Interleukin (IL)-17A favorably modulates inflammatory disorders including DN. In this study, we examined whether IL-17A deficiency affected the autophagy process in the kidneys of mice with streptozotocin (STZ)-induced DN. Methods The autophagic response of IL-17A to STZ-induced nephrotoxicity was evaluated by analyzing STZ-induced functional and histological renal injury in IL-17A knockout (KO) mice. Results IL-17A KO STZ-treated mice developed more severe nephropathy than STZ-treated wild-type (WT) mice, with increased glomerular damage and renal interstitial fibrosis at 12 weeks. IL-17A deficiency also increased the up-regulation of proinflammatory cytokines and fibrotic gene expression after STZ treatment. Meanwhile, autophagy-associated proteins were induced in STZ-treated WT mice. However, IL-17A KO STZ-treated mice displayed a significant decrease in protein expression. Especially, the levels of LC3 and ATG7, which play crucial roles in autophagosome formation, were notably decreased in the IL-17A KO STZ-treated mice compared with their WT counterparts. Conclusions IL-17 deficiency aggravates of STZ-induced DN via attenuation of autophagic response. Our study demonstrated that IL-17A mediates STZ-induced renal damage and represents a potential therapeutic target in DN.

Autophagy in renal fibrosis: Protection or promotion?

“…Compared with WT mice, IL-17A-KO-STZtreated mice have significantly lower levels of LC3 and ATG7, which play a key role in autophagosome formation. Thus, these findings highlight that IL-17 deficiency exacerbates STZ-induced interstitial fibrosis by attenuating the autophagic response (Kim et al, 2021). These studies demonstrate that enhanced autophagy of fibrosis in the thylakoid region and interstitium during DKD fibrosis promotes the progression of fibrosis.…”

Screening and Identification of Hub Genes in the Development of Early Diabetic Kidney Disease Based on Weighted Gene Co-Expression Network Analysis

“…KEGG signal pathway enrichment analysis suggested that DEGs were mainly enriched in the cytokine receptor interaction pathway, namely, the C-C receptor interaction, the IL-17 signaling pathway, and viral protein interaction with cytokines and cytokine receptors. Kim et al and Mohamed et al (26,27) found that the IL-17 signaling pathway is essential for early DKD and that the application of IL-17A could prevent, treat, and reverse DKD effectively. Cytokine biology tends to be complex.…”

Identification of Oxidative Stress-Related Biomarkers in Diabetic Kidney Disease

“…In a clinical study, IL-17 expression decreased in DKD patients with disease progression [ 20 ]. In addition, in the STZ-treated mouse model of IL-17 knockout, it was found that IL-17A knockout mice aggravated renal inflammation and fibrosis by inhibiting autophagy [ 21 ]. Although the specific role of IL-17 in diabetic nephropathy is still unknown, it is clear that IL-17 has a significant role in the onset of diabetic nephropathy.…”