Once women enter menopause, they lose their protection from hypertension, cardiovascular disease and progressive renal disease when compared to age-matched premenopausal women and age-matched men. In the first funding period, we found that experimentally mimicking the state of menopause by ovariectomy in several species, increased the density of angiotensin type 1 receptors (AT1R) in the adrenal and kidney, which are two key target tissues of the renin angiotensin system (RAS) that are critical to the control of blood pressure. Furthermore, increased AT1R numbers resulted in increased sensitivity to angiotensin II (Ang II) in both these tissues. In pathological models of aging and hypertension associated renal disease, estrogen deficiency was associated with increased renal injury, including interstitial fibrosis and glomerulosclerosis, and increased NAD(P)H oxidase activity, which was prevented by 17p-estradiol (?2) replacement. We also recently found that ?2 deficiency reduced the expression of the newly discovered member of the RAS, namely, angiotensin converting enzyme 2 (ACE2), which hydrolyzes Ang II to the vasodilator heptapeptide, Ang-(l-T). The actions of ACE2 are thought to counter those of ACE. In fact, ACE2 has been shown to be cardioprotective in the heart;however, much less is known regarding the role of ACE2 in the kidney. In this competitive renewal, we will focus on the signaling pathways leading to tubulointerstitial fibrosis (TIP) in the unilateral ureteral obstruction model (UUO) in the mouse, which is a widely used model of accelerated TIP. The RAS plays a major role in these signaling pathways since angiotensin converting enzyme (ACE) inhibitors and AT1R antagonists are widely used clinically to inhibit disease progression in these pathologies. We will investigate ?2 regulation of ACE-dependent (Aim 1), AT1R-dependent (Aim 2) and ACE2-dependent (Aim 3) pathways in the pathological processes leading to TIP that contribute to the renal protection afforded the estrogen replete female. In a mouse model of UUO, we will test the hypothesis that ?2 loss in the obstructed kidney promotes TIF by increasing renal oxidative stress through augmentation of ACE- and AT1R-dependent superoxide (Or) accumulation and attenuation of ACE2-dependent inhibition of superoxide accumulation through nitric oxide (NO) generation;?2 loss also promotes TIP by stimulating extracellular matrix accumulation through increased ACE- and AT1R-dependent transforming growth factor pi (TGF-pl)-Smad signaling pathways. The signal transduction pathways leading to TIP in UUO share many similarities with a number of chronic renal diseases of various etiologies. Thus, specifically investigating the RAS-dependent mechanisms underlying the effects of ?2 loss on TIP progression in UUO may lead to a greater understanding of the mechanisms involved in progressive renal disease in postmenopausal women and ultimately, may lead to the development of novel therapeutics for treating this major public health problem in both men and women.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-B (02))
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Murthy, Mahadev
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Georgetown University
Internal Medicine/Medicine
Schools of Medicine
United States
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Sandberg, Kathryn; Ji, Hong; Einstein, Gillian et al. (2016) Is immune system-related hypertension associated with ovarian hormone deficiency? Exp Physiol 101:368-74
Ji, Hong; Zheng, Wei; Wu, Xie et al. (2016) Aging-related impairment of urine-concentrating mechanisms correlates with dysregulation of adrenocortical angiotensin type 1 receptors in male Fischer rats. Am J Physiol Regul Integr Comp Physiol 310:R513-21
Sandberg, Kathryn; Ji, Hong; Hay, Meredith (2015) Sex-specific immune modulation of primary hypertension. Cell Immunol 294:95-101
Ji, Hong; Zheng, Wei; Li, Xiangjun et al. (2014) Sex-specific T-cell regulation of angiotensin II-dependent hypertension. Hypertension 64:573-82
Liu, Jun; Yosten, Gina L C; Ji, Hong et al. (2014) Selective inhibition of angiotensin receptor signaling through Erk1/2 pathway by a novel peptide. Am J Physiol Regul Integr Comp Physiol 306:R619-26
Wang, Dan; Wang, Cheng; Wu, Xie et al. (2014) Endothelial dysfunction and enhanced contractility in microvessels from ovariectomized rats: roles of oxidative stress and perivascular adipose tissue. Hypertension 63:1063-9
Sandberg, Kathryn; Ji, Hong (2013) Is ? the ? dog in estrogen receptor-mediated protection from hypertension? Hypertension 61:1153-4
Sandberg, Kathryn; Samson, Willis K; Ji, Hong (2013) Decoding noncoding RNA: da Vinci redux? Circ Res 113:240-1
Liu, Jun; Sharma, Nikhil; Zheng, Wei et al. (2011) Sex differences in vasopressin Výýý receptor expression and vasopressin-induced antidiuresis. Am J Physiol Renal Physiol 300:F433-40
Ji, Hong; Zheng, Wei; Wu, Xie et al. (2010) Sex chromosome effects unmasked in angiotensin II-induced hypertension. Hypertension 55:1275-82

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