Men and male rats are predisposed to hypertensive renal injury compared to women or female rats. The mechanisms responsible for these gender differences are unclear; however, recent studies have strongly implicated androgens. The overall goal of this proposal is to investigate the mechanisms responsible for androgen-induced renal injury. We propose that the gender difference in renal injury is mediated by both hemodynamic and non-hemodynamic mechanisms. We hypothesize that the hemodynamic mechanism involves androgen-induced activation of the renin angiotensin II (Ang II) system (RAS), leading to increases in proximal sodium (Na) reabsorption, reduction of Na at the macula densa and decreases in afferent resistance. Non-hemodynamic mechanisms are mediated by Ang II stimulation of cytokines, growth factors and transcription factors to produce extracellular matrix. Ang II will also stimulate oxidative stress which further activates transcription factors and causes glomerular injury.
In Aim 1 the hypothesis will be tested that androgens mediated via the androgen receptor are responsible for promoting glomerular injury in hypertensive male SHR, by increasing testosterone to promote injury, using androgen receptor antagonists to prevent injury , and triple therapy to determine the role of androgen-mediated increases in BP alone.
In Aim 2 the hypothesis will be tested that androgens stimulate the RAS to increase Ang II which leads to increases in cytokines (such as TGF-B), extracellular matrix proteins, and transcription factors (AP- 1, NF-KB). The hypothesis will be tested in SHR and cyclically stretched mesangial cells (MSCs) (to mimic increased glomerular pressure) using biochemical, molecular and genetic array techniques to measure cytokines, extracellular matrix, activation of transcription factors with and without Ang II antagonists.
In Aim 3, the hypothesis will be tested that Ang II will promote injury in males by producing oxidative stress and will be studied using SHR and stretched MSCs in the presence or absence of antioxidants and factors known to be activated by oxidative stress (superoxide, isoprostanes, heme oxygenase-1, peroxynitrite, etc) will be measured by biochemical assays.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069194-04
Application #
6797891
Study Section
Special Emphasis Panel (ZHL1-CSR-E (S1))
Program Officer
Barouch, Winifred
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$296,040
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
Dalmasso, Carolina; Maranon, Rodrigo; Patil, Chetan et al. (2016) Cardiometabolic Effects of Chronic Hyperandrogenemia in a New Model of Postmenopausal Polycystic Ovary Syndrome. Endocrinology 157:2920-7
Regensteiner, Judith G; Golden, Sherita; Huebschmann, Amy G et al. (2015) Sex Differences in the Cardiovascular Consequences of Diabetes Mellitus: A Scientific Statement From the American Heart Association. Circulation 132:2424-47
Reckelhoff, Jane F (2014) Gender medicine: ""in a perfect world …"". Clin Ther 36:1870-1872
Soljancic, Andrea; Ruiz, Arnaldo Lopez; Chandrashekar, Kiran et al. (2013) Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury. Am J Physiol Regul Integr Comp Physiol 304:R951-8
Maranon, Rodrigo; Reckelhoff, Jane F (2013) Sex and gender differences in control of blood pressure. Clin Sci (Lond) 125:311-8
Ojeda, Norma B; Hennington, Bettye Sue; Williamson, Danielle T et al. (2012) Oxidative stress contributes to sex differences in blood pressure in adult growth-restricted offspring. Hypertension 60:114-22
Lima, Roberta; Wofford, Marion; Reckelhoff, Jane F (2012) Hypertension in postmenopausal women. Curr Hypertens Rep 14:254-60
Lu, Yan; Fu, Yiling; Ge, Ying et al. (2012) The vasodilatory effect of testosterone on renal afferent arterioles. Gend Med 9:103-11
Davis, Deborah D; Ruiz, Arnaldo Lopez; Yanes, Licy L et al. (2012) Testosterone supplementation in male obese Zucker rats reduces body weight and improves insulin sensitivity but increases blood pressure. Hypertension 59:726-31
Li, Jing; LaMarca, Babbette; Reckelhoff, Jane F (2012) A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model. Am J Physiol Heart Circ Physiol 303:H1-8

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