期刊
AGING-US
卷 12, 期 10, 页码 9139-9150出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.103183
关键词
chronic kidney disease; cardiovascular disease; Klotho; indoxyl sulfate; macrophage polarization
资金
- Zhejiang Nature Science Fund [LY16H150005]
- Medical Scientific Research Foundation of Zhejiang Province [WKJ-ZJ-1401]
- Zhejiang Medical and Health Science and Technology Project [2016RCB001]
- Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents
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 TNF alpha, IL-6, and IL-1 beta, 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.
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