Local angiotensin II and transforming growth factor-beta 1 in renal fibrosis of rats

Studies have demonstrated that local angiotensin II (Ang II) generation is enhanced in repairing kidney and that ACE inhibition or AT(1) receptor bloc kade attenuates renal fibrosis. The localization of ACE and Ang II receptor s and their relationship to collagen synthesis in the injured kidney, howev er, remain uncertain. Using a rat model of renal injury with subsequent fib rosis created with chronic elevations in circulating aldosterone (ALDO), we examined the distribution and binding density of ACE and Ang II receptors in repairing kidneys, as well as their anatomic relationship to transformin g growth factor-beta 1 (TGF-beta 1) mRNA, type I collagen mRNA, collagen ac cumulation, and myofibroblasts. Two groups of animals (n=7 in each group) w ere studied: (1) normal rats served as controls, and (2) uninephrectomized rats received ALDO (0.75 mu g/h SC) and 1% NaCl in drinking water for 6 wee ks. Compared with control rats, in ALDO-treated rats we found (1) significa ntly (P<0.01) increased blood pressure, reduced plasma renin activity, and increased plasma creatinine levels, (2) diffuse fibrosis in both renal cort ex and medulla, (3) abundant myofibroblasts at these sites of fibrosis, (4) significantly increased (P<0.01) binding density of ACE and Ang II recepto rs (60% AT(1), 408 AT(2)) at the sites of fibrosis, and (5) markedly increa sed (P<0.01) expression of TGF-beta 1 and type I collagen mRNAs at these sa me sites. Thus, in this rat model of renal repair, the enhanced expression of ACE, Ang II receptors, and TGF-beta 1 is associated with renal fibrosis. Ang II generated at the sites of repair appears to have autocrine/paracrin e functions in the regulation of renal fibrous tissue formation alone or th rough its stimulation of TGF-beta 1 synthesis.