PHARMACOLOGICAL CONTROL OF ANGIOTENSIN-II AMELIORATES RENAL-DISEASE WHILE REDUCING RENAL TGF-BETA IN EXPERIMENTAL MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS

We evaluated the effect of blocking angiotensin II (AngII) on the deve lopment of proteinuria and glomerular injury in antithymocyte serum (A TS) glomerulonephritis. Disease was induced in Sprague-Dawley rats by a single intravenous injection of rabbit ATS. Three groups of rats wer e considered: group 1 (n = 13), ATS rats with no therapy; group 2 (n = 13), ATS rats treated with angiotensin-converting enzyme inhibitor (4 0 mg/L lisinopril in the drinking water); and group 3 (n = 13), ATS ra ts treated with AngII receptor antagonist (50 mg/L-158,809 in the drin king water). Treatment started 3 hours after ATS Injection and lasted 4 days. An additional group of control rats (group 4, n = 13) received preimmune serum. At day 4, ATS rats developed proteinuria (46 +/- 5 m g/d v control 12 +/- 1 mg/d; P < 0.01), which was prevented by both li sinopril and L-158,809 (14 +/- 0.2 mg/d and 15 +/- 1.6 mg/d, respectiv ely, P < 0.01 vATS). Systolic blood pressure was comparable in ATS rat s and in controls (119 +/- 4 mm Hg v 120 +/- 2 mm Hg). Systolic brood pressure values were significantly decreased after either lisinopril o r L-158,809 (104 +/- 3 mm Hg and 101 +/- 5 mm Hg, respectively; P < 0. 01 VATS). Serum creatinine levels were similar in all groups. Quantita tion of proliferating cells and macrophages by analysis of proliferati ng cell nuclear antigen-positive and EDI-positive cells/glomerular cro ss-section showed a marked increase in proliferating cell nuclear anti gen-positive cells in glomeruli of ATS rats over controls (12.6 +/- 0. 5 cells/glomerular cross-section v 1.9 +/- 0.2 cells/glomerular cross- section; P < 0.01), which was significantly (P < 0.01) prevented by bo th treatments (lisinopril, 5.7 +/- 1.0 cells/glomerular cross-section; L-158,809, 4.8 +/- 1.5 cells/glomerular cross-section). The increase in ED1-positive cells (10 +/- 0.7 cells/glomerular cross-section v con trols, 1.8 +/- 0.2 cells/glomerular cross-section; P < 0.01) was also significantly (P < 0.01) reduced by lisinopril and L-158,809 (4.1 +/- 0.7 cells/glomerular cross-sections and 2.6 +/- 0.6 cells/glomerular c ross-section, respectively). Blocking of AngII activity prevented almo st completely the formation of microaneurysms in ATS rats (percent of glomeruli with microaneurysms: ATS, 11.5% +/- 3.5%; ATS + lisinopril, 0.4% +/- 0.2%; ATS + L-158,809, 0.8% +/- 0.8%; controls, 0%). Because AngII is a potent inducer of renal transforming growth factor-beta (TG F-beta), a cytokine involved in the regulation of cell proliferation, matrix deposition, and monocyte migration (which is overexpressed in t he kidney of ATS rats), we then evaluated the effect of AngII inhibito rs on renal gene expression of TGF-beta 1 and on urinary TGF beta-1. T GF-beta 1 mRNA levels in kidneys of ATS rats were 3.6-fold higher than those of controls and were reduced by 46% and 32% after treatment wit h lisinopril and 1-158,809, respectively. Urinary TGF-beta 1 excretion increased in ATS (37.3 +/- 6.0 ng/d v controls, 13.8 +/- 3.4 ng/d; P < 0.01) but was normalized by lisinopril and L-158,809 (7.6 +/- 1.9 ng /d and 6.4 +/- 0.4 ng/d, respectively; P < 0.01). Thus, in ATS, blocki ng AngII synthesis prevents proteinuria and reduces glomerular cell pr oliferation and inflammatory cell infiltration, possibly by reducing e xcessive renal TGF-beta synthesis. These findings may be relevant for future strategies in the treatment of human mesangioproliferative glom erulonephritis. (C) 1998 by the National Kidney Foundation, Inc.