Dehydroandrographolide facilitates M2 macrophage polarization by downregulating DUSP3 to inhibit sepsis‐associated acute kidney injury

Abstract

Abstract Background Sepsis is perceived as lethal tissue damage and significantly increases mortality in combination with acute kidney injury (AKI). M2 macrophages play important roles in the secretion of anti‐inflammatory and tissue repair mediators. We aimed to study the role of Dehydroandrographolide (Deh) in sepsis‐associated AKI in vitro and in vivo through lipopolysaccharide (LPS)‐induced macrophages model and cecal ligation and puncture‐induced AKI mice model, and to reveal the mechanism related to M2 macrophage polarization. Methods Enzyme‐linked immunosorbent assay kits were used to assess the levels of inflammatory factors. Expression of markers related to M1 macrophages and M2 macrophages were analyzed. Additionally, dual specificity phosphatase 3 (DUSP3) expression was tested. Cell apoptosis was evaluated by flow cytometry analysis and terminal‐deoxynucleotidyl transferase‐mediated nick end labeling staining. Moreover, renal histological assessment was performed by using hematoxylin and eosin staining. Results Deh reduced inflammation of THP‐1‐derived macrophages exposed to LPS. Besides, Deh induced the polarization of M1 macrophages to M2 and downregulated DUSP3 expression in THP‐1‐derived macrophages under LPS conditions. Further, DUSP3 overexpression reversed the impacts of Deh on the inflammation and M2 macrophages polarization of THP‐1‐derived macrophages stimulated by LPS. Additionally, human proximal tubular epithelial cells (HK‐2) in the condition medium from DUSP3‐overexpressed THP‐1‐derived macrophages treated with LPS and Deh displayed decreased viability and increased apoptosis and inflammation. The in vivo results suggested that Deh improved the renal function, ameliorated pathological injury, induced the polarization of M1 macrophages to M2, suppressed inflammation and apoptosis, and downregulated DUSP3 expression in sepsis‐induced mice. Conclusion Deh facilitated M2 macrophage polarization by downregulating DUSP3 to inhibit septic AKI.

Keywords

• acute kidney injury
• dehydroandrographolide
• DUSP3
• inflammation
• M2 macrophage polarization