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 established. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenetic 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 nephrectomy, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT1 receptor blocker candesartan cilexetil (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined regularly, and at week 16, systolic BP, plasma total cholesterol, and triglyceride (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; GS: 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) macrophages (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) was 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 AT1 receptor blockade, together with the inhibition of IL-2 synthesis, is more effective in the prevention of GS than a single treatment alone.
Hamar
P
P
Department of Pathophysiology, International Nephrological Research and Training Center, Semmelweis University, Budapest, Hungary. hampet@net.sote.hu
Peti-Peterdi
J
J
Rázga
Z
Z
Kovács
G
G
Heemann
U
U
Rosivall
L
L
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004656:Enalapril / Q000627:therapeutic use; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D007107:Immune System / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D011507:Proteinuria / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects; D016559:Tacrolimus / Q000627:therapeutic use; D013777:Tetrazoles / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D013777:Tetrazoles; D014280:Triglycerides; D004656:Enalapril; D002784:Cholesterol; C081643:candesartan; D016559:Tacrolimus