Department of Rheumatology, Immunology and Allergy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
EBioMedicine. 2023 Jun;92:104607. doi: 10.1016/j.ebiom.2023.104607. Epub 2023 May 30.
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.
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-κB p65 using siRNA, and blocking Hypoxia-inducible factor-1α (HIF-1α) using YC-1 in mice and HIF-1α Decoy in HK2 cells were investigated to explore the possible signaling pathway involved in IL-17C regulation.
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-κB pathway.
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.
The National Natural Science Foundation of China (81770741, 81700601 and 81870504).
白细胞介素-17C（IL-17C）是白细胞介素-17 细胞因子家族的成员，在肾脏疾病中发挥致病作用。我们之前的研究表明，IL-17C 中和抗体的预先给药可减轻急性肾损伤（AKI，一种常见的与急性炎症相关的肾脏疾病）。在这项研究中，我们探讨了 IL-17C 阻断后缺血再灌注（IR）是否对 AKI 具有治疗作用，以及 IL-17C 是否参与糖尿病肾病（DN，一种主要的与慢性炎症相关的肾脏疾病）的发病机制。
12 周龄雄性 C57BL/6JGpt 小鼠在再灌注后 3 小时用 IL-17C 中和抗体或正常 IgG 对照抗体治疗。评估肾脏损伤、炎症和氧化应激。此外，我们检测了 DN 患者和 db/db 小鼠的肾脏 IL-17C 表达，并评估了 db/db 小鼠中 IL-17C 中和对白蛋白尿、系膜基质积聚和足细胞丢失的影响。使用 siRNA 敲低 NF-κB p65，使用 YC-1 在小鼠和 HIF-1α 诱饵在 HK2 细胞中阻断 Hypoxia-inducible factor-1α (HIF-1α)，以探讨 IL-17C 调节的可能信号通路。
我们发现延迟的 IL-17C 中和对肾缺血再灌注损伤（IRI）具有相似的肾保护作用。此外，DN 患者和 db/db 小鼠的肾脏 IL-17C 表达增加，而 IL-17C 阻断显著减轻了 DN，同时减轻了白蛋白尿、系膜基质积聚和足细胞丢失。此外，IL-17C 中和在肾 IRI 和 DN 小鼠中均显著抑制下游促炎细胞因子的表达、炎症细胞浸润和 Th17/IL-17A 激活。机制研究表明，缺氧或高糖诱导的 IL-17C 上调主要由 NF-κB 途径介导。
IL-17C 参与 AKI 和 DN 的发病机制，抑制 IL-17C 可能成为 AKI 和 DN 的治疗策略。
国家自然科学基金（81770741、81700601 和 81870504）。
