Exogenous PRAS40 reduces KLF4 expression and alleviates hypertrophic scar fibrosis and collagen deposition through inhibiting mTORC1.

To identify the anti-fibrosis effect of PRAS40 in scar, and its potential mechanism. We constructed a rat model of hypertrophic scarthat was locally injected the PRAS40 overexpression adenoviruses, mTORC1 inhibitor MHY1485 and activator rapamycin, and further observed the pathological changes of skin tissue and the severity of fibrosis by HE, Masson and sirius red staining, and analyzed the deposition of a-SMA and collagen I by western blot and immunofluorescence test. Meanwhile, the co-localization of KLF4 with a-SMA and type I collagen was analyzed, as well as the regulatory effect of PRAS40 on KLF4. In addition, we also verified whether the inhibition of scar fibrosis by PRAS40 is related to mTORC1, and whether the upregulation of KLF4 is related to mTORC1. The results showed that the expression of PRAS40 was low and p-PRAS40 was high in scar skin tissue. After local injection of PRAS40 overexpression adenovirus, the expression of PRAS40 in skin tissue was increased. The overexpression of PRAS40 can inhibit scar skin fibrosis and reduce the content of a-SMA and collagen I. Further mechanism analysis confirms that the inhibitory effect of PRAS40 on skin fibrosis is related to mTORC1, and PRAS40 inhibits the activation of mTORC1. The expression of KLF4 is relatively low in scar tissue. PRAS40 administration upregulated the expression of KLF4, which is related to mTORC1 PRAS40 significantly improves fibrosis of scar skin tissue and increases the expression of KLF4 in scars. The anti-fibrotic effect of PRAS40 depends on mTORC1. • Exogenous PRAS40 improved the scar fibrosis in the injured tissues of HS rats. • mTORC1 activation accelerates fibrosis degree in the injured skin. PRAS40 is also an inhibitor of mTORC1 inactivation, so we believe that the effect of PRAS40 on scar fibrosis is related to mTORC1. • KLF4 is an important regulator in the development of fibrosis. • Consistent with the previous report, we found a high expression of KLF4 in skin tissues , while after HS modeling, KLF4 was downregulated. Interestingly, PRAS40 could modulate the KLF4 expression, and this effect was also related to mTORC1. [ABSTRACT FROM AUTHOR]