Diabetes is one of the leading causes of death in the United States and a well-recognized independent risk factor for the development of cardiovascular (CV) and end-stage renal disease in premenopausal and postmenopausal women. Diabetic women exhibit a greater prevalence of cardiovascular and renal pathologies as compared to age-matched males or non-diabetic females. The recent classification of cardiorenal syndrome in diabetic patients emphasizes the occurrence of simultaneous injury and/or dysfunction in the heart and kidney. Importantly, the combined renal and cardiac dysfunction or failure in diabetic hypertensive women with estrogen depletion significantly contributes to the poor prognosis for these patients. The absence of an in vivo experimental model of cardiorenal syndrome in hypertensive diabetic females limits our ability to elucidate the underlying mechanisms of this syndrome, as well as the development of more effective therapeutic approaches. This application seeks to establish an experimental model of diabetic cardiorenal syndrome in the congenic mRen2.Lewis rat that reflects the coexistence of cardiac and renal dysfunction/failure in diabetic hypertensive women with reduced estrogen. The studies will also establish the role of the novel estrogen receptor GPR30 to attenuate the development and progression of the cardiorenal syndrome which may reveal new therapeutic approaches to reduce CV disease in women.

Public Health Relevance

Cardiovascular disease (CVD) is leading cause of death for women in the US and the identification of the cardiorenal syndrome (the interrelationship between cardiac and renal dysfunction) may have important implications regarding the early diagnosis and treatment of CVD in women, particularly with diabetes as an additional complicating factor. The proposed project addresses a critical issue in the cardiorenal syndrome through the development of a robust experimental model in the diabetic hypertensive mRen2.Lewis strain and assessment of the novel estrogen receptor GPR30.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Schools of Medicine
United States
Zip Code
Alzayadneh, Ebaa M; Chappell, Mark C (2014) Nuclear expression of renin-angiotensin system components in NRK-52E renal epithelial cells. J Renin Angiotensin Aldosterone Syst :
Wilson, Bryan A; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) The ins and outs of angiotensin processing within the kidney. Am J Physiol Regul Integr Comp Physiol 307:R487-9
Alzayadneh, Ebaa M; Chappell, Mark C (2014) Angiotensin-(1-7) abolishes AGE-induced cellular hypertrophy and myofibroblast transformation via inhibition of ERK1/2. Cell Signal 26:3027-35
Chappell, Mark C (2013) Of diabetic mice and ACE2: a new biomarker of renal disease? Am J Physiol Renal Physiol 305:F970-2
Gwathmey, TanYa M; Alzayadneh, Ebaa M; Pendergrass, Karl D et al. (2012) Novel roles of nuclear angiotensin receptors and signaling mechanisms. Am J Physiol Regul Integr Comp Physiol 302:R518-30
Yamaleyeva, Liliya M; Gilliam-Davis, Shea; Almeida, Igor et al. (2012) Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Renal Physiol 302:F1374-84