Intact Fibroblast Growth Factor 23 Regulates Chronic Kidney Disease-Induced Myocardial Fibrosis by Activating the Sonic Hedgehog Signaling Pathway

作者全名："Li, Lanlan; Gan, Hua"

作者地址："[Li, Lanlan; Gan, Hua] Chongqing Med Univ, Dept Nephrol, Affiliated Hosp 1, Chongqing, Peoples R China"

通信作者："Gan, H (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF THE AMERICAN HEART ASSOCIATION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000858504900001

JCR分区：Q1

影响因子：5.4

年份：2022

卷号：11

期号：18

开始页：　

结束页：　

文献类型：Article

关键词：cardiac fibroblasts; chronic kidney disease; intact fibroblast growth factor 23; myocardial fibrosis; Sonic Hedgehog signaling

摘要："Background Clinically, myocardial fibrosis is one of the most common complications caused by chronic kidney disease (CKD). However, the potential mechanisms of CKD-induced myocardial fibrosis have not been clarified. Methods and Results In our in vivo study, a rat model of CKD with 5/6 nephrectomy was established. The CKD model was treated with the glioma 1 (Gli-1) inhibitor GANT-61, and myocardial fibrosis and serum intact fibroblast growth factor 23 levels were assessed 16 weeks after nephrectomy. Finally, we found that Gli-1 and Smoothened in the Sonic Hedgehog (Shh) signaling pathway were activated and that collagen-1 and collagen-3, which constitute the fibrotic index, were expressed in CKD myocardial tissue. After administering the Gli-1 inhibitor GANT-61, the degree of myocardial fibrosis was reduced, and Gli-1 expression was also inhibited. We also measured blood pressure, cardiac biomarkers, and other indicators in rats and performed hematoxylin-eosin staining of myocardial tissue. Furthermore, in vitro studies showed that intact fibroblast growth factor 23 promoted cardiac fibroblast proliferation and transdifferentiation into myofibroblasts by activating the Shh signaling pathway, thereby promoting cardiac fibrosis, as manifested by increased expression of the Shh, Patch 1, and Gli-1 mRNAs and Shh, Smoothened, and Gli-1 proteins in the Shh signaling pathway. The protein and mRNA levels of other fibrosis indicators, such as alpha-smooth muscle actin, which are also markers of transdifferentiation, collagen-1, and collagen-3, were increased. Conclusions On the basis of these results, intact fibroblast growth factor 23 promotes CKD-induced myocardial fibrosis by activating the Shh signaling pathway."

基金机构：National Science and Technology Support "Twelfth Five-Year" Project; Ministry of Education's Special Research Fund for Doctoral Programs

基金资助正文：This research was supported by the National Science and Technology Support "Twelfth Five--Year" Project and the Ministry of Education's Special Research Fund for Doctoral Programs.