PDGF receptor kinase blocker AG1295 attenuates interstitial fibrosis in rat kidney after unilateral obstruction.

The current study was designed to investigate possible effects of the platelet-derived growth factor (PDGF) receptor kinase blocker AG1295 on the development of interstitial fibrosis in rats with unilateral ureteral obstruction (UUO), monitored by ED-A+ fibronectin expression, the number of macrophages, and the presence of myofibroblasts as visualized by immunohistochemistry with monoclonal antibodies (mAb) IST9, mAb ED1, and mAb 1A4, respectively; interstitial fibrosis was quantified by Sirius-Red staining and computer-aided image analysis. Without AG1295 treatment, the Sirius-Red stained area of the control kidneys comprised 6.8 +/- 1.3% of the totally inspected area and increased to 19.0 +/- 1.9% in animals by 14 days and to 23.4 +/- 1.7% by 21 days after UUO. The number of macrophages increased from 4.3 +/- 1.1 in controls to 16.6 +/- 2.6 in animals at 14 days and to 23.2 +/- 4.4 at 21 days after UUO. This was accompanied by an increase in both ED-A+ fibronectin deposition and alpha-smooth muscle actin expression. Treatment with AG1295 (12 mg/kg body weight, daily i.p.) significantly reduced interstitial fibrosis as verified by a smaller Sirius-Red stained area (15.7 +/- 1.9% in animals at 14 days and 17.0 +/- 0.7% at 21 days after UUO) and also by a reduced number of macrophages (12.8 +/- 1.4 in animals at 14 days and 15.5 +/- 3.8 at 21 days after UUO), and by the ED-A+ fibronectin deposition and the number of cells positive for alpha-smooth muscle actin. The study indicates that the PDGF receptor kinase blocker AG1295 is able to decrease interstitial fibrosis in the rat UUO model significantly. The diminution of early fibrosis mediators, i.e., macrophages, ED-A+ fibronectin, and myofibroblast phenotype, points to a modulated fibrosis process via a blockade of PDGF actions.