Abstract
Receptor tyrosine kinases (RTKs) play important roles in the pathogenic processes of kidney fibrosis. However, the pathophysiological roles of recepteur d’origine nantais (RON), one of the receptor tyrosine kinases, have not yet been defined. We investigated whether the activation or sequence-specific small interfering RNA (siRNA) suppression of RON could regulate epithelial mesenchymal transition (EMT) and the expression of pro-fibrotic markers, and its underlying molecular mechanisms. Stable cell lines and transient transfection for RON and the transfected cells of siRNA for RON were developed to investigate the molecular mechanisms in human kidney proximal tubular epithelial (HK-2) and interstitial fibroblasts (NRK49F) cells. RON overexpression induced EMT and increased expression of fibrosis-related proteins such as N-cadherin, vimentin, transforming growth factor-β (TGFβ), αSMA, and fibronectin in HK-2 and NRK49F cells. RON overexpression increased various RTKs and the phosphorylation of Src (Y416) and Smad, while inhibition of RON by siRNA attenuated the expression of EMT- and fibrosis-related proteins and decreased RTKs such as insulin-like growth factor receptor (IGFR), fibroblast growth factor receptor 1 (FGFR1), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), as well as the phosphorylation of Src and Smad pathways. siRNA silencing of Src also attenuated the expression of IGFR, FGFR1, VEGFR, and PDGFR. Inhibition of RON can exert an anti-fibrotic effect by the inhibition of EMT and other RTKs through control of Src and Smad pathways in HK-2 and NRK49F cells.
Highlights
Chronic kidney disease (CKD) can lead to the development of kidney dysfunction and require costly therapy with dialysis or transplantation, and, is associated with high rates of morbidity and mortality [1]
We studied the expression of receptor tyrosine kinase recepteur d’origine nantais (RON) in the kidney of a unilateral ureteral obstruction (UUO) mouse model
We demonstrated the regulation of epithelial mesenchymal transition (EMT) and fibrotic markers, as well as Receptor tyrosine kinases (RTKs) and Src phosphorylation, by RON overexpression and knockdown
Summary
Chronic kidney disease (CKD) can lead to the development of kidney dysfunction and require costly therapy with dialysis or transplantation, and, is associated with high rates of morbidity and mortality [1]. Compared to an average cost of treating disease, CKD has a 1.8-fold burden on medical costs due to complications such as diabetes, hypertension, stroke, heart disease, and infection. CKD is closely related to aging and chronic diseases, and its socio-economic burden continues to increase [3,4]. In this context, slowing the progression of kidney disease can prevent various complications, save on medical costs, and lead to patients living healthier lives
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