Coinhibition of immune and renin-angiotensin systems reduces the pace of glomerulosclerosis in the rat remnant kidney

The development of progressive glomerulosclerosis (GS) has been attributed to a number of humoral and hemodynamic factors, however, neither the exact pathomechanism nor the prevention and treatment have been clearly establish ed. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenet ic factors. According to our working hypothesis, a combination therapy with the inhibition of RAS and IL-2 system may be more potent in the prevention of the progression of GS than a monotherapy. After 5/6 subtotal nephrectom y, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT(1) receptor blocker candesartan cilexe til (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined r egularly, and at week 16, systolic BP, plasma total cholesterol, and trigly ceride (TG) levels were measured and kidneys were harvested for morphologic and immunohistochemical analysis. Combination therapy was more effective ( proteinuria: CA + T: 29.3 +/- 12.8 mg/24 h, E + T: 31.3 +/- 13.0 mg/24 h; G S: CA + T: 10.7 +/- 4.1%, E + T: 8.3 +/- 4.6%, P < 0.01) than monotherapy ( proteinuria: T: 49.3 +/- 17.3 mg/24 h, CA: 53.2 +/- 18.1 mg/24 h, E: 51.1 /- 26.6 mg/24 h; GS: T: 10.9 +/- 4.4%, CA: 23.8 +/- 4%, E: 14.2 +/- 5.3%, P < 0.05, with control values of proteinuria: 77.6 +/- 27.1 mg/24 h and GS: 28 +/- 2.9%). The number of infiltrating ED-1 (rat macrophage marker) macro phages (T: 161.5 +/- 51.2 cells/field of view, CA: 203.6 +/- 102.3, E: 178. 6 +/- 35.3, CA + T: 140.2 +/- 63.2, E + T:128.2 +/- 75.6), and CD-5+ (rat T cell marker)T lymphocytes (CA + T: 261.5 +/- 103.6, E + T: 236 +/- 94.8) w as significantly reduced by the treatment protocols (controls: ED-1:356 +/- 100, CD-5: 482.9 +/- 154.5). These results indicate that an inhibition of RAS either with angiotensin-converting enzyme or AT, receptor blockade, tog ether with the inhibition of IL-2 synthesis, is more effective in the preve ntion of GS than a single treatment alone.