Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis

Abstract

Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be caused by the proliferation of renal inherent cells, including glomerular epithelial cells, mesangial cells, and endothelial cells, along with defective kidney repair, renal interstitial fibroblasts activation, and extracellular matrix deposition. Receptor tyrosine kinases (RTKs) regulate a variety of cell physiological processes, including metabolism, growth, differentiation, and survival. Many studies from in vitro and animal models have provided evidence that RTKs play important roles in the pathogenic process of renal fibrosis. It is also showed that tyrosine kinases inhibitors (TKIs) have anti-fibrotic effects in basic research and clinical trials. In this review, we summarize the evidence for involvement of specific RTKs in renal fibrosis process and the employment of TKIs as a therapeutic approach for renal fibrosis.

Keywords: discoidin domain receptors; epidermal growth factor receptor; fibroblast growth factor receptor; growth arrest-specific gene; insulin-like growth factor receptor; platelet-derived growth factors receptor; receptor tyrosine kinases; renal fibrosis; tyrosine kinase inhibitors; vascular endothelial growth factors receptor.

Figure 1

Signaling mechanisms of epidermal growth factor receptor (EGFR) transactivation in renal fibrosis. Upon stimulation with G protein-coupled receptor (GPCR) ligands (i.e., angiotension II), some intracellular events. Including activation of Src and protein kinase C (PKC), production of reactive oxygen species (ROS) and influx of calcium are initiated. Src can directly induce EGFR phosphorylation/activation via a ligand-independent mechanism. Src and other intracellular signaling molecules can also induce EGFR transactivation via a ligand dependent mechanism involving activation of MMPs and subsequent cleavage of proEGFR ligands to release their soluble forms. These soluble ligands bind to EGFR and induce its dimerization and activation, which, in turn, sequentially activates the ERK1/2, production of TGF-β1 and activation of TGF-β signaling pathway.