A Study on the Role of Wip1 in Renal Fibrosis by Modulating Macrophage Phenotype

Background. Renal fibrosis is the result of chronic kidney diseases, the exploration of the pathogenesis of renal fibrosis and the development of effective treatment methods have become major challenges. Aims. To investigate the effect of wild-type p53-induced phosphatase 1 (Wip1) on macrophage phenotype regulation and the role played in renal fibrosis. Methods. RAW264.7 macrophages were stimulated by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) or interleukin 4 (IL-4) to differentiate into M1 or M2 macrophages. Lentivirus vectors were transduced into RAW264.7 macrophages to construct the cell lines that overexpressed or silenced Wip1, respectively. Furthermore, E-cadherin, Vimentin, and alpha-SMA levels of primary renal tubular epithelial cells (RTECs) were measured after co-culture with macrophages overexpressed or silenced by Wip1. Results. Macrophages stimulated by LPS plus IFN-gamma differentiated into M1 macrophages with high expression of iNOS and TNF-alpha, while those stimulated by IL-4 differentiated into M2 macrophages with high expression of Arg-1 and CD206. Increased expression of iNOS and TNF-alpha was observed in macrophages transduced with Wip1 RNA interference, while an increased expression of Arg-1 and CD206 was observed in macrophages transduced with Wip1 overexpressed vector, indicating that RAW264.7 macrophages could be transformed into M2 macrophages after Wip1 overexpression, and transformed into M1 macrophages by down-regulating Wip1. In addition, the E-cadherin mRNA level decreased and Vimentin and alpha-SMA increased in RTECs co-cultured with Wip1 overexpressed macrophages compared to the control group. Conclusion. Wip1 may participate in the pathophysiological process of renal tubulointerstitial fibrosis by transforming macrophages into the M2 phenotype. (c) 2023 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.