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Life Sci. 2019 Jun 14:116570. doi: 10.1016/j.lfs.2019.116570. [Epub ahead of print]

Klotho restrain RIG-1/NF-κB signaling activation and monocyte inflammatory factor release under uremic condition.

Author information

1
Department of Nephrology, The key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing 400037, PR China.
2
Department of Nephrology, The key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing 400037, PR China. Electronic address: zhaojh@tmmu.edu.cn.

Abstract

AIMS:

Systemic inflammation is a main hallmark of chronic kidney disease (CKD), but the underlying mechanisms of pathogenesis of CKD-associated systemic inflammation is unclear. Current study was designed to investigate the relationship between indoxyl sulphate (IS) and CKD-associated systemic inflammation along with the protective effects of Klotho in CKD.

METHODS:

IS serum levels from patients were detected by high-performance liquid chromatography (HPLC), and Serum Klotho, IL-6 and TNF-α were measured separately by ELISA and Real-Time PCR analysis. Monocytes were incubated with or without Klotho, while the expressions of retinoic acid-inducible gene I (RIG-I) and NF-κB were analyzed through Western blot assay. Heterozygous kl/kl (kl/+) mice or WT mice were treated with 5/6 renal damage. Thereafter, the CKD mice were intraperitoneally injected with recombinant Klotho protein or PBS.

KEY FINDINGS:

It shows that in 286 CKD patients, the serum levels of inflammatory factors were positively related with IS, but negatively related with Klotho. Klotho significantly inhibited IS-induced RIG-I/NF-κB activation and productions of both IL-6 and TNF-α in cultured monocytes. In vivo, along with the increase of IS and decrease of Klotho in the serum, the activation of RIG-I/NF-κB signaling was observed in peripheral blood monocytes in both CKD mice and patients. Notably, higher levels of IL-6 and TNF-α were detected in kl+/- mice given CKD. Klotho administration has evidently attenuated RIG-I/NF-κB activation in monocytes and systemic inflammation in CKD mice.

SIGNIFICANCE:

The findings suggest that Klotho can suppress CKD-associated systemic inflammation through inhibiting IS-induced RIG-1/NF-κB activation and monocyte inflammatory factor release.

KEYWORDS:

Chronic kidney disease; Indoxyl sulphate; Inflammation; Klotho

PMID:
31207307
DOI:
10.1016/j.lfs.2019.116570

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