期刊
KIDNEY INTERNATIONAL
卷 65, 期 3, 页码 846-859出版社
ELSEVIER SCIENCE INC
DOI: 10.1111/j.1523-1755.2004.00462.x
关键词
animal models; autoantibodies; cytokines; lupus nephritis; systemic lupus erythematosus; transforming growth factor beta
资金
- NIAMS NIH HHS [P30 AR47363, R01 AR050797, R01 AR50797, R01 AR047322, R01 AR047322-03, R01 AR050797-02, P30 AR047363-050002, P30 AR047363, R01 AR47322] Funding Source: Medline
Background. Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, are used to control hypertension. In patients and animals with primary nephropathies, these agents improve renal function more than that would be expected from their control of hypertension. Here, we examine the effects of treatment with captopril on lupus nephritis and discuss the potential mechanism(s) by which this agent exerts its renoprotective effects. Methods. Lupus-prone, NZB/NZW F1 and MRL-lpr/lpr, mice were treated with captopril or with a control antihypertensive agent, verapamil. Mice were monitored for nephritis, and their sera and tissues analyzed for cytokine and transforming growth factor-beta (TGF-beta) expression. Results. Captopril treatment delayed the onset of proteinuria when administered to prenephritic mice, whereas verapamil did not. Captopril treatment also retarded disease progression when given to lupus mice that had early disease, and even reversed severe proteinuria in at least some older animals with advanced disease. It reduced chronic renal lesions, but had no effect on autoantibody production. The improvement in renal disease correlated with reduced TGF-beta expression, particularly of the TGF-beta1 and TGF-beta2 isoforms, in the kidneys. Interestingly, in vivo or in vitro exposure to captopril reduced splenic levels of type 2 cytokines, interleukin (IL)-4 and IL-10, suggesting a possible role of the immune system in captopril-mediated disease modulation. Conclusion. Since type 2 cytokines are known to promote lupus glomerulosclerosis, decreased IL-4 and IL-10 production in captopril-treated mice may be related to this agent's renoprotective effects. We argue here that ACE inhibitors not only act as selective TGF-beta inhibitors, but also as selective immunomodulators, to improve lupus nephritis.
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