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

P. Hamar, János Peti-Peterdi, Zsolt Rázga, Gergely Kovács, Uwe Heemann, L. Rosivall

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Abstract

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.

Original languageEnglish
JournalJournal of the American Society of Nephrology
Volume10
Issue number1 SUPPL. 11
Publication statusPublished - Jan 1999

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Renin-Angiotensin System
Kidney
Proteinuria
Interleukin-2
Peptidyl-Dipeptidase A
T-Lymphocytes
Macrophages
Angiotensin Type 1 Receptor
Enalapril
candesartan cilexetil
Angiotensin Receptor Antagonists
Tacrolimus
Clinical Protocols
Nephrectomy
Triglycerides
Therapeutics
Hemodynamics
Cholesterol
Lipids
Serum

ASJC Scopus subject areas

  • Nephrology

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Coinhibition of immune and renin-angiotensin systems reduces the pace of glomerulosclerosis in the rat remnant kidney. / Hamar, P.; Peti-Peterdi, János; Rázga, Zsolt; Kovács, Gergely; Heemann, Uwe; Rosivall, L.

In: Journal of the American Society of Nephrology, Vol. 10, No. 1 SUPPL. 11, 01.1999.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Peti-Peterdi, János

AU - Rázga, Zsolt

AU - Kovács, Gergely

AU - Heemann, Uwe

AU - Rosivall, L.

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