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

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.

• Authors: Ting He, Jiachuan Xiong, Yinghui Huang, Changling Zheng, Yong Liu, Xianjin Bi, Chi Liu, Wenhao Han, Ke Yang, Tangli Xiao, Xinli Xu, Yanlin Yu, Yunjian Huang, Jingbo Zhang, Bo Zhang, Jinghong Zhao
• Journal: Life sciences (Life Sci) Vol. 231 Pg. 116570 (Aug 15 2019) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 31207307 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-6
• NF-kappa B
• Receptors, Immunologic
• Tumor Necrosis Factor-alpha
• Glucuronidase
• Klotho Proteins
• RIGI protein, human
• DEAD Box Protein 58
• Indican

Topics

• Adult
• Animals
• Blotting, Western
• DEAD Box Protein 58 (blood)
• Female
• Glucuronidase (blood, pharmacology)
• Humans
• Indican (blood)
• Inflammation (blood, pathology)
• Interleukin-6 (blood)
• Kidney (metabolism)
• Klotho Proteins
• Male
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Monocytes (metabolism, pathology)
• NF-kappa B (blood)
• Receptors, Immunologic
• Renal Insufficiency, Chronic (blood, pathology)
• Signal Transduction
• THP-1 Cells
• Tumor Necrosis Factor-alpha (blood)
• Uremia (blood, pathology)