Tyrosine kinases inhibition by Imatinib slows progression in chronic anti-thy1 glomerulosclerosis of the rat

摘要

Background Chronic progressive mesangioproliferative nephropathy represents a major cause of end-stage renal disease worldwide. Until now, effective approaches to stop or even slow its progression are limited. We tested the effects of an inhibitor of PDGF receptor, abl and c-kit tyrosine kinases, Imatinib, in a chronic progressive model of mesangioproliferative glomerulosclerosis. Methods Anti-thy1 glomerulosclerosis was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, according to the degree of proteinuria, animals were stratified and assigned to chronic glomerulosclerosis (cGS) and cGS plus Imatinib (10?mg/kg body weight/day). In week 20, renoprotective actions of Imatinib were analyzed by a set of functional, histological and molecular biological parameters. Results Untreated cGS rats showed elevation of systolic blood pressure and marked progression in proteinuria, renal fibrosis, cell infiltration, cell proliferation and function lost. Administration of Imatinib went along significantly with lower systolic blood pressure (?10?mmHg) and proteinuria (?33%). Imatinib administration was paralled by significant reductions in tubulointerstitial accumulation of matrix proteins (?44%), collagen I deposition (?86%), expression of TGF-beta1 (?30%), production of fibronectin (?23%), myofibroblast differentiation (?87%), macrophage infiltration (?36%) and cell proliferation (?45%), respectively. In comparison with untreated cGS animals, Imatinib therapy lowered also blood creatinine (?41%) and blood urea concentrations (?36%) and improved creatinine clearance (+25%). Glomerular fibrotic changes were lowered moderately by Imatinib. Conclusions Therapy with Imatinib limits the progressive course of chronic anti-thy1 glomerulosclerosis towards tubulointerstitial fibrosis and renal insufficiency. This was paralleled by direct and indirect sign of TGF-β1 and PDGF inhibition. The findings suggest that the pharmacological principal of inhibition of tyrosine kinases with drugs such as Imatinib might serve as approach for limiting progression of human mesangioproliferative glomerulosclerosis.