Role of P311 in interleukin-1α-induced epithelial to myofibroblast transition in kidney tubular epithelial cells

Abstract

Tubular epithelial-myofibroblast transition (TEMT) is an important process in renal tubulointerstitial fibrosis. Interleukin-1α (IL-1α) and transforming growth factor-β1 (TGF-β1) have been demonstrated to be key inducers of TEMT. In mouse embryonic fibroblast cells (NIH3T3), P311 protein induces phenotypic changes that are consistent to myofibroblast transformation. In the present study, we investigated the role of P311 gene and protein as well as potential mechanisms underlying TEMT in normal rat kidney tubular epithelial cells (NRK52E). Morphological and molecular changes were determined in NRK52E cells that were treated with IL-1α and/or P311 antibodies. The results showed that the NRK52E cells triggered by IL-1α became fibroblast-like cells, exhibiting hypertrophy of elongated and fusiform-shaped cells. IL-1α induced a time-dependent increase in P311 gene expression in NRK52E cells, with a peak time at 4 days. The expression levels of P311 gene were positively correlated with α-SMA and TGF-β1 gene expression levels. Anti-P311 antibody inhibited P311 and α-SMA expression in the presence of IL-1α. In contrast, anti-P311 antibody increased the expression of TGF-β1 gene in cells cultured with IL-1α. Therefore, P311 gene, together with α-SMA and TGF-β1 genes, was induced in the process of TEMT. P311 protein triggered by interleukin-1α may promote TEMT through a TGF-β1-independent pathway.

P311 induces the transdifferentiation of epidermal stem cells to myofibroblast-like cells by stimulating transforming growth factor β1 expression

“…However, little is known regarding the roles performed by and regulation of EpMyT during skin wound healing. Recent studies using rat kidney epithelial cell lines have shown that P311 may promote IL-1α-induced EMT via a TGFβ1-independent pathway [31] and that it may inhibit TGFβ1-induced EMT by blocking the Smad/ILK pathways [32]. Furthermore, our recent in-vivo study showed that P311 promotes renal fibrosis via the TGFβ1/Smad signaling [33].…”

Pharmacological functions of salidroside in renal diseases: facts and perspectives

“…Lei et al found that at concentrations of 10, 50 and 100 μmol/L, salidroside could reverse the hypertrophy and elongation of proximal renal tubular epithelial cells induced by cobalt chloride in hypoxic rats, showing the appearance of myoblasts. Salidroside inhibits the expression of TGF-β1 and HIF-1α, reduces the increase of extracellular matrix such as α-SMA, collagen I and fibronectin, and inhibits the transdifferentiation of hypoxic renal tubular epithelial cells-myofibroblasts (Zhang et al, 2010).…”

A negative feedback loop involving NF-κB/TIR8 regulates IL-1β-induced epithelial- myofibroblast transdifferentiation in human tubular cells

“…IL-1 is capable of inducing morphological and phenotypic transdifferentiation of a normal rat tubular epithelial cell line into myofibroblast-like cells (Vesey et al 2002). IL-1β, as a much stronger inducer of nuclear factor (NF)-κB response, interacts with IL-1 receptor (IL-1R) to induce EMT by activating the IL-1/IL-1R/NF-κB signaling pathway (Dinarello and Wolff 1993;Gasse et al 2007;Zhang et al 2015). The NF-κB complex is usually inactive and located in the cytoplasm while bound to IκB inhibitor proteins; however, after activation of IL-1/IL-1R/NF-κB signaling, NF-κB is activated and translocates to the nucleus, where it forms the p65/p50 complex to control target gene transcription (Gupta et al 2010;Zheng et al 2011).…”