Tranilast ameliorates renal tubular damage in unilateral ureteral obstruction

Purpose: We determined whether tranilast, the anti-allergic agent N-(3, 4-d imethoxyciannamoyl)-anthranilic acid, would diminish renal transforming gro wth factor-beta (TGF-beta) levels in unilateral ureteral obstruction and co ncomitantly affect renal tubular apoptosis and proliferation in that condit ion. Materials and Methods: Tranilast (150 mg./kg.) was administered to rats 1 d ay before unilateral ureteral obstruction and each day thereafter. Kidneys were harvested day 14 after unilateral ureteral obstruction, Tissue TGF-bet a was measured by bioassay using mink lung epithelial cells. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating c ell nuclear antigen and the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay, respectively. Fibrosis w as assessed by measuring collagen deposition with trichrome stained slides. Results: TGF-beta bioassay showed that obstructed kidneys in controls conta ined significantly higher mean TGF-beta plus or minus standard deviation th an unobstructed kidneys in controls (73.7 +/- 13.6 versus 14.1 +/- 5.5 pg./ mg. tissue) and tranilast significantly decreased tissue TGF-beta in obstru cted kidneys (15.9 +/- 4.8 pg./mg, tissue). The terminal deoxynucleotidyl t ransferase mediated deoxyuridine triphosphate nick end labeling assay demon strated that obstructed kidneys in controls had significantly more mean tub ular apoptosis than the unobstructed counterparts (36.6 +/- 6.7 versus 5.8 +/- 5.5 nuclei per high power field) and tranilast significantly decreased mean renal tubular apoptosis in obstructed kidneys (16.2 +/- 1.7 nuclei per high power field). In addition, immunostaining proliferating cell nuclear antigen showed that obstructed kidneys in controls had significantly more m ean renal tubular proliferation than unobstructed kidneys (20.7 +/- 3.4 ver sus 6.2 +/- 2.1 per high power field) and tranilast significantly increased proliferating renal tubules in obstructed and unobstructed kidneys (26.5 /- 8.3 and 14.5 +/- 3.4 per high power field, respectively). Control obstru cted kidneys exhibited significantly more fibrosis, which was also blunted by tranilast. Conclusions: Tranilast significantly decreases tissue TGF-beta, resulting i n a reduction ill tubular apoptosis and an increase in tubular proliferatio n. This finding suggests that tranilast is a promising agent for preventing renal tubular damage in unilateral ureteral obstruction.