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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Center Core Grants (P30)
Project #
1P30AR047363-01
Application #
6447619
Study Section
Special Emphasis Panel (ZAR1)
Project Start
2001-03-15
Project End
2006-02-28
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Rydyznski, Carolyn E; Cranert, Stacey A; Zhou, Julian Q et al. (2018) Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers. Cell Rep 24:3367-3373.e4
Carroll, Kaitlin R; Elfers, Eileen E; Stevens, Joseph J et al. (2018) Extending Remission and Reversing New-Onset Type 1 Diabetes by Targeted Ablation of Autoreactive T Cells. Diabetes 67:2319-2328
Goodman, Michael Aaron; Arumugam, Paritha; Pillis, Devin Marie et al. (2018) Foamy Virus Vector Carries a Strong Insulator in Its Long Terminal Repeat Which Reduces Its Genotoxic Potential. J Virol 92:
Hinks, Anne; Marion, Miranda C; Cobb, Joanna et al. (2018) Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis. Arthritis Rheumatol 70:957-962
Gupta, Varsha; Tangpricha, Vin; Yow, Eric et al. (2018) Analysis of relationships between 25-hydroxyvitamin D, parathyroid hormone and cathelicidin with inflammation and cardiovascular risk in subjects with paediatric systemic lupus erythematosus: an Atherosclerosis Prevention in Paediatric Lupus Erythematosus Lupus Sci Med 5:e000255
Rochman, Yrina; Dienger-Stambaugh, Krista; Richgels, Phoebe K et al. (2018) TSLP signaling in CD4+ T cells programs a pathogenic T helper 2 cell state. Sci Signal 11:
Rueda, Cesar M; Rodríguez-Perea, Ana Lucia; Moreno-Fernandez, Maria et al. (2017) High density lipoproteins selectively promote the survival of human regulatory T cells. J Lipid Res 58:1514-1523
Forsberg, Matthew H; Ciecko, Ashley E; Bednar, Kyle J et al. (2017) CD137 Plays Both Pathogenic and Protective Roles in Type 1 Diabetes Development in NOD Mice. J Immunol 198:3857-3868
Moncrieffe, Halima; Bennett, Mark F; Tsoras, Monica et al. (2017) Transcriptional profiles of JIA patient blood with subsequent poor response to methotrexate. Rheumatology (Oxford) 56:1542-1551
Bertaux-Skeirik, Nina; Wunderlich, Mark; Teal, Emma et al. (2017) CD44 variant isoform 9 emerges in response to injury and contributes to the regeneration of the gastric epithelium. J Pathol 242:463-475

Showing the most recent 10 out of 214 publications