IL-17C Neutralization Protects the Kidney Against Acute Injury and Chronic Injury

Abstract

Background: Interleukin-17C (IL-17C), a member of the IL-17 cytokine family, plays a pathogenic role in kidney diseases. Our previous studies have shown that pre-administration of IL-17C neutralizing antibody protected against acute renal ischemia/reperfusion injury (IRI) in mice. However, whether post-IR of IL-17C blockade has therapeutic effects on AKI and whether IL-17C is involved in the pathogenesis of diabetic nephropathy (DN), a major type of chronic kidney disease, remain unknown. Methods: 12-week-old male C57BL/6JGpt mice were treated with IL-17C neutralizing antibody or normal IgG1 control antibody at 3 hours after reperfusion. Renal injury, inflammation and oxidative stress were assessed. Additionally, we examined renal IL-17C expression in patients with DN and db/db mice and evaluated albuminuria, mesangial matrix accumulation and podocyte loss in db/db mice with IL-17C neutralization. To further explore the possible signaling pathway involved in IL-17C regulation, NF-κB and HIF-1α pathways were investigated in vitro and in vivo. Findings: Renal dysfunction, oxidative stress and renal tubular injury were remarkably blunted by post-IR administration of an IL-17C neutralizing antibody in mice with renal IRI. Additionally, we found that renal IL-17C expression was significantly increased in patients with DN and db/db mice while IL-17C blockade significantly attenuated diabetic nephropathy, accompanied with blunted albuminuria, mesangial matrix accumulation and podocyte loss. Moreover, IL-17C neutralization significantly repressed the expression of downstream proinflammatory cytokines, inflammatory cells infiltration and Th17/IL-17A activation both in mice with renal IRI and DN. Mechanistical studies demonstrated that hypoxia and high glucose both resulted in IL-17C upregulation in renal tubular cells through NF-κB pathway other than HIF-1α pathway. Interpretation: IL-17C participates in the pathogenesis of AKI and DN and inhibition of IL-17C shows potential as a therapeutic strategy for AKI and DN. Funding Information: This work was supported by the National Natural Science Foundation of China (81770741, 81700601 and 81870504). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: Protocols involving the use of human medical information and kidney biopsy samples were approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. The study was conducted in accordance with the World Medical Association Declaration of Helsinki, and all subjects signed the informed consent. All animal experiments and procedures were approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital.