Angiotensin-converting enzyme inhibitors (ACEIs), such as captopril, are widely used to control hypertension in patients who have chronic renal disease. ACEIs improve renal function in patients with chronic renal disease, however, than would be expected from their suppression of hypertension. ACEI-induced improvement in renal function is associated with decreased renal TGF-beta expression and matrix deposition. We anticipate that ACEIs may have a similar effect on TGF-beta production, renal fibrosis and end stage renal disease in patients with lupus. However, because TGF-beta can inhibit T and B cell activation and auto-antibody productions, an ACEI-induced decrease in TGF-beta may exacerbate auto-antibody-mediated disease in lupus by enhancing auto-antibody production. Consequently, this proposal will explore potential therapeutic and damaging effects of ACEIs in SLE, inflammatory component of lupus nephritis, its continued presence enhances renal matrix deposition and fibrosis. To test this hypothesis we will: 1) evaluate autoantibody responses and renal disease in lupus-prone mice treated with ACEIs; and 2) generate and characterize mice that have kidney-specific deletion of the Tgfb1 gene. These mice will be used in future to determine the effect of TGF-beta deletion on lupus nephritis. Lupus-prone and control mice will be treated with captopril or a control anti-hypertensive agent; the effect on blood pressure, renal functions, renal histology, renal immune and collagen deposition will be determined. These changes will be correlated with TGF-beta expression in kidneys and spleens, and serum auto-antibodies. We will then generate mice that have renal-specific Tgfb1 gene deletion, and characterize their phenotype, specifically for any inflammatory changes in kidneys and other organs. The broad objectives of this proposal are to understand the role of TGF- beta in the pathogenesis of lupus nephritis, to explore how manipulation of in vivo TGF-beta can influence lupus, and to elucidate the mechanism and clinical utility of ACEIs in lupus. Delineation of pathways that cause matrix deposition in kidneys, but do not affect T and B cell activation, may lead to treatment strategies that improve end stage renal disease in SLE.
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