Klotho alleviates indoxyl sulfate-induced heart failure and kidney damage by promoting M2 macrophage polarization.

Jing Lv,Minjia Wang,Jin Chen,Fei Yan

doi:10.18632/aging.103183

Abstract

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.

Highlights

Chronic kidney disease (CKD) and acute kidney injury (AKI) have a high global prevalence and economic burden [1]
We found that Indoxyl sulfate (IS) stimulated the production of several pro-inflammatory cytokines (TNFα, IL-6, and IL-1β) in THP-1-derived macrophages (Figure 1A)
We found that treatment of THP-1-derived macrophages with 2 mM IS resulted in an increase in the proportion of HLA-DR+ cells (M1 macrophages) (Figure 1D, 1E)

Summary

Introduction

Chronic kidney disease (CKD) and acute kidney injury (AKI) have a high global prevalence and economic burden [1]. Cardiovascular disease (CVD) is a serious complication in patients with CKD and AKI, and is the main cause of death among patients on dialysis [5,6,7]. Macrophages are the main contributors to the inflammatory response in CKD and AKI [10,11,12]. They play a dual role in AKI through polarization towards the pro-inflammatory M1 (classically activated) and antiinflammatory M2 (alternatively activated) phenotypes [4, 13, 14]. Previous studies have demonstrated that M2 macrophage polarization is important for cardiac repair and recovery from kidney injury in AKI patients [15, 16]

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