Department of General Practice, Zhejiang Hospital, Hangzhou 310013, Zhejiang, P.R. China.
Department of Critical Care Medicine, Zhejiang Hospital, Hangzhou 310013, Zhejiang, P.R. China.
Aging (Albany NY). 2020 May 28;12(10):9139-9150. doi: 10.18632/aging.103183.
Indoxyl sulfate (IS) is a protein-bound uremic toxin that can accumulate in patients with chronic kidney disease (CKD) or acute kidney injury (AKI) and cause kidney and cardiac dysfunction. Klotho is an anti-aging protein that has reno- and cardio-protective effects. We investigated whether Klotho could alleviate IS-induced heart failure and kidney damage by regulating macrophages, which play a key role in the inflammatory response in CKD and AKI. Treatment of THP-1-derived macrophages with IS induced the production of the pro-inflammatory cytokines TNFα, IL-6, and IL-1β, and stimulated M1 polarization. Additionally, IS induced downregulation of Klotho expression in macrophages. Overexpression of Klotho suppressed the IS-induced inflammatory response in macrophages by stimulating M2 polarization. It also alleviated IS-induced cardiac hypertrophy and renal fibrosis in mice. A reduction in IS-induced phosphorylation of NF-kB p65 was observed in response to Klotho overexpression, suggesting that Klotho alleviates kidney and cardiac injury by inactivating NF-kB signaling and promoting macrophage M2 polarization.
硫酸吲哚酚（IS）是一种与蛋白质结合的尿毒症毒素，可在慢性肾脏病（CKD）或急性肾损伤（AKI）患者中蓄积，并导致肾脏和心脏功能障碍。Klotho 是一种抗衰老蛋白，具有肾和心脏保护作用。我们研究了 Klotho 是否可以通过调节巨噬细胞来减轻 IS 诱导的心力衰竭和肾脏损伤，巨噬细胞在 CKD 和 AKI 的炎症反应中发挥关键作用。用 IS 处理 THP-1 衍生的巨噬细胞会诱导产生促炎细胞因子 TNFα、IL-6 和 IL-1β，并刺激 M1 极化。此外，IS 诱导巨噬细胞中 Klotho 表达下调。Klotho 的过表达抑制了 IS 诱导的巨噬细胞炎症反应，刺激了 M2 极化。它还减轻了 IS 诱导的小鼠心脏肥大和肾脏纤维化。观察到 Klotho 的过表达可减少 IS 诱导的 NF-kB p65 磷酸化，表明 Klotho 通过抑制 NF-kB 信号通路和促进巨噬细胞 M2 极化来减轻肾脏和心脏损伤。
