Abstract
Evidence has been shown that indoxyl sulfate (IS) could impair kidney and cardiac functions. Moreover, macrophage polarization played important roles in chronic kidney disease and cardiovascular disease. IS acts as a nephron-vascular toxin, whereas its effect on macrophage polarization during inflammation is still not fully elucidated. In this study, we aimed to investigate the effect of IS on macrophage polarization during lipopolysaccharide (LPS) challenge. THP-1 monocytes were incubated with phorbol 12-myristate-13-acetate (PMA) to differentiate into macrophages, and then incubated with LPS and IS for 24 h. ELISA was used to detect the levels of TNFα, IL-6, IL-1β in THP-1-derived macrophages. Western blot assay was used to detect the levels of arginase1 and iNOS in THP-1-derived macrophages. Percentages of HLA-DR-positive cells (M1 macrophages) and CD206-positive cells (M2 macrophages) were detected by flow cytometry. IS markedly increased the production of the pro-inflammatory factors TNFα, IL-6, IL-1β in LPS-stimulated THP-1-derived macrophages. In addition, IS induced M1 macrophage polarization in response to LPS, as evidenced by the increased expression of iNOS and the increased proportion of HLA-DR+ macrophages. Moreover, IS downregulated the level of β-catenin, and upregulated the level of YAP in LPS-stimulated macrophages. Activating β-catenin signaling or inhibiting YAP signaling suppressed the IS-induced inflammatory response in LPS-stimulated macrophages by inhibiting M1 polarization. IS induced M1 macrophage polarization in LPS-stimulated macrophages via inhibiting β-catenin and activating YAP signaling. In addition, this study provided evidences that activation of β-catenin or inhibition of YAP could alleviate IS-induced inflammatory response in LPS-stimulated macrophages. This finding may contribute to the understanding of immune dysfunction observed in chronic kidney disease and cardiovascular disease.
Highlights
Chronic kidney disease (CKD) is defined as functional abnormalities of the kidney, or decreased glomerular filtration rate (GFR, < 60 mL/min/1.73 m 2) for more than 3 months (Chala et al 2019; Shiba and Shimokawa 2011)
Previous study indicated that CKD is commonly associated with the inflammation (Engel et al 2019), and macrophages are the main contributors to the inflammatory response to CKD (Guiteras et al 2016)
LPS significantly induced the production of pro-inflammatory cytokines TNFα, IL-6, IL-1β in THP-1-derived macrophages (Fig. 1a–f)
Summary
Chronic kidney disease (CKD) is defined as functional abnormalities of the kidney, or decreased glomerular filtration rate (GFR, < 60 mL/min/1.73 m 2) for more than 3 months (Chala et al 2019; Shiba and Shimokawa 2011). Cardiovascular disease (CVD) is a group of problems of the heart or blood vessels, and is a serious complication of CKD (Weiner 2009). CKD is a serious risk factor for CVD, indicating that kidney disease and CVD are closely interconnected (Yang et al 2010). Kidney damage cause dysfunction of heart tissue, eventually leading to dysfunction of both organs (Liu et al 2014). Previous study indicated that CKD is commonly associated with the inflammation (Engel et al 2019), and macrophages are the main contributors to the inflammatory response to CKD (Guiteras et al 2016). Macrophage polarization plays a vital role in the progression of CKD (Engel and Chade 2019). Renal injury activated the inflammation response pathway, and promoted M1 macrophage
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