EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA-1 AND TYPE-IV COLLAGEN IN THE RENAL TUBULOINTERSTITIUM IN EXPERIMENTAL DIABETES - EFFECTS OF ACE-INHIBITION

Transforming growth factor-beta (TGF-beta) and the renin-angiotensin s ystem (RAS) have both been implicated in the pathogenesis of glomerulo sclerosis in diabetic kidney disease, However, tubulointerstitial path ology may also be an important determinant of progressive renal dysfun ction in diabetic nephropathy. In the present study, we investigated t ubulointerstitial injury, TGF-beta 1 expression, and the effect of blo cking the RAS by inhibition of ACE, We randomized 36 male SD rats to c ontrol and diabetic groups, Diabetes was induced in 24 rats by adminis tration of streptozotocin; 12 diabetic rats were further randomized to receive the ACE inhibitor ramipril (3 mg/l drinking water), At 6 mont hs, experimental diabetes was associated with tubulointerstitial damag e, a 70% increase in expression of TGF-beta 1 (P < 0.05 vs, control) a nd a 120% increase in alpha 1 (IV) collagen gene expression (P < 0.01 vs. control). In situ hybridization demonstrated a diffuse increase in both TGF-beta 1 and alpha 1 (IV) collagen mRNA in renal tubules, In a ddition, intense expression of both transcripts was noted in regions o f focal tubular dilatation, Administration of the ACE inhibitor ramipr il prevented tubulointerstitial injury and the overexpression of TGF-b eta 1 and alpha 1 (IV) collagen mRNA. Changes in gene expression were accompanied by parallel changes in immunostaining for TGF-beta 1 and t ype IV collagen, The observed beneficial effects of ramipril on the tu bulointerstitium in experimental diabetes suggest that this mechanism may contribute to the therapeutic effect of ACE inhibitors in diabetic nephropathy.