IL-17C neutralization protects the kidney against acute injury and chronic injury

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 attenuated acute kidney injury (AKI, a common acute inflammation associated renal disease). In this study, we explored whether post-ischemia reperfusion (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 inflammation-associated kidney disease. Methods 12-week-old male C57BL/6JGpt mice were treated with IL-17C neutralizing antibody or normal IgG control antibody at 3 h 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. Knockdown of NF-& kappa;B p65 using siRNA, and blocking Hypoxia-inducible factor-1 & alpha; (HIF-1 & alpha;) using YC-1 in mice and HIF-1 & alpha; Decoy in HK2 cells were investigated to explore the possible signaling pathway involved in IL-17C regulation. Findings We found that delayed IL-17C neutralization had similar reno-protective effects on renal ischemia-reperfusion injury (IRI). Additionally, renal IL-17C expression was increased in patients with DN and db/db mice, while IL-17C blockade significantly attenuated DN, accompanied with blunted albuminuria, mesangial matrix accumulation, and podocyte loss. Moreover, IL-17C neutralization significantly repressed the expression of downstream pro-inflammatory cytokines, inflammatory cell infiltration, and Th17/IL-17A activation both in mice with renal IRI and DN. Mechanistical studies demonstrated that hypoxia or high glucose-induced IL-17C up-regulation was predominantly mediated by NF-& kappa;B 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 The National Natural Science Foundation of China (81770741, 81700601 and 81870504). Copyright & COPY; 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 2023;92: Published https://doi.org/10. 1016/j.ebiom.2023. 104607

Automated summary

In this study, the researchers investigated the therapeutic effects of IL-17C blockade on AKI and DN. They found that delayed IL-17C neutralization can protect against renal ischemia-reperfusion injury and attenuate DN in mice. They also discovered that IL-17C expression is increased in patients with DN and IL-17C blockade can reduce albuminuria, mesangial matrix accumulation, and podocyte loss in DN.