Background: Increasing evidence indicates that epidermal growth factor receptor (EGFR) has a pathogenic role in renal fibrosis. Currently no effective treatment can completely halt the progression of chronic kidney disease (CKD). This study was undertaken to investigate the renoprotective effects of erlotinib, a tyrosine kinase inhibitor that can block EGFR activity in the progression of CKD and the mechanisms involved.
Methods: Sprague Dawley rats with 5/6 nephrectomy were administered either erlotinib or vehicle from 2 weeks after surgery and for a period of 8 weeks. Blood pressure, proteinuria and serum creatinine were measured periodically. Renal morphological investigations were performed at sacrifice. In vitro, we used normal human mesangial cells (NHMCs) and human proximal tubular cells to investigate the inhibitory effects of erlotinib on renal fibrosis-associated signaling pathways by western blotting.
Results: Erlotinib treatment significantly blunted the progression of CKD as evidenced by reduced levels of serum creatinine, proteinuria and renal cortical profibrogenic genes and scores of glomerulosclerosis and tubulointerstitial damage. Tubulointerstitial macrophage infiltration and multiple pro-inflammatory cytokine gene expression levels were also attenuated by erlotinib treatment. In vitro, heparin-binding epidermal growth factor-like growth factor-induced Akt and extracellular-regulated kinase (ERK) 1/2 activation in normal human mesangial cells and human proximal tubular cells was inhibited by pretreatment with erlotinib.
Conclusions: EGFR blocking by erlotinib protected against renal fibrosis in 5/6 nephrectomized rats via inhibition of Akt and ERK 1/2 signaling pathways, which are associated with renal fibrosis. Erlotinib also has anti-inflammatory properties, which may contribute to its renoprotective effects. Erlotinib represents a potential novel therapeutic strategy for the treatment of CKD.