. The incidence of hypertension and vascular dysfunction is high in women with systemic lupus erythematosus (SLE). Growing evidence suggests that inflammatory cytokines promote hypertension by mechanisms yet to be elucidated. One possible mechanism is that chronic inflammation promotes oxidative stress and endothelial dysfunction leading to altered renal hemodynamics and reduced renal pressure natriuresis. Activation of the transcription factor PPARgamma reduces blood pressure, cytokine expression, and oxidative stress. Our preliminary data indicates that renal PPARgamma expression is reduced in a mouse model of SLE (NZBWF1). This suggests that protective effects of PPARgamma may be reduced in SLE. Although inflammatory cytokines, oxidative stress, and PPARgamma are altered in SLE, their role in causing hypertension and renal microvascular dysfunction is not clear. Our central hypothesis is that during SLE, inflammatory cytokines TNFalpha and IL-6, and reduced expression of PPARgamma promote oxidative stress leading to endothelial dysfunction. This leads to increased renal vascular resistance and hypertension. Preliminary data from our laboratory indicates that blood pressure is elevated and endothelial function is impaired in the NZBWF1 model. The central hypothesis will be tested in the following specific aims. (1) SLE causes increased renal vascular resistance and an impaired renal pressure natriuresis relationship which contributes to increased blood pressure. (2) TNFalpha and IL-6 are important mediators of endothelial dysfunction, impaired renal-pressure natriuresis, and increased blood pressure during SLE. (3) Elevated levels of reactive oxygen species are important mediators of altered renal hemodynamics and blood pressure during SLE. (4) Reductions in renal PPARgamma promote oxidative stress and inflammation which contribute to the renal vascular dysfunction and hypertension during SLE. Relevance: Systemic lupus erythematosus (SLE) is an autoimmune disorder that predominantly affects women. Women with SLE are likely to have high blood pressure and kidney disease. Very little is understood about the factors that cause high blood pressure during SLE. This proposal will begin to address some of the mechanisms that contribute to hypertension during SLE.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085907-04
Application #
7799870
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Thrasher, Terry N
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$293,237
Indirect Cost
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Gilbert, Emily L; Ryan, Michael J (2014) Impact of early life ovariectomy on blood pressure and body composition in a female mouse model of systemic lupus erythematosus. Am J Physiol Regul Integr Comp Physiol 307:R990-7
Mathis, Keisa W; Broome, Hanna J; Ryan, Michael J (2014) Autoimmunity: an underlying factor in the pathogenesis of hypertension. Curr Hypertens Rep 16:424
Gilbert, Emily L; Mathis, Keisa W; Ryan, Michael J (2014) 17?-Estradiol protects against the progression of hypertension during adulthood in a mouse model of systemic lupus erythematosus. Hypertension 63:616-23
Ryan, Michael J (2013) An update on immune system activation in the pathogenesis of hypertension. Hypertension 62:226-30
Imig, John D; Ryan, Michael J (2013) Immune and inflammatory role in renal disease. Compr Physiol 3:957-76
Mathis, Keisa W; Venegas-Pont, Marcia; Flynn, Elizabeth R et al. (2013) Hypertension in an experimental model of systemic lupus erythematosus occurs independently of the renal nerves. Am J Physiol Regul Integr Comp Physiol 305:R711-9
Mathis, Keisa W; Venegas-Pont, Marcia; Masterson, C Warren et al. (2012) Oxidative stress promotes hypertension and albuminuria during the autoimmune disease systemic lupus erythematosus. Hypertension 59:673-9
Dhaun, Neeraj; Kluth, David C (2012) Oxidative stress promotes hypertension and albuminuria during the autoimmune disease systemic lupus erythematosus. Hypertension 59:e47; author reply e48
Yanes, Licy L; Lima, Roberta; Moulana, Mohadetheh et al. (2011) Postmenopausal hypertension: role of 20-HETE. Am J Physiol Regul Integr Comp Physiol 300:R1543-8
Ryan, Michael J; Gilbert, Emily L; Glover, Porter H et al. (2011) Placental ischemia impairs middle cerebral artery myogenic responses in the pregnant rat. Hypertension 58:1126-31

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