Establishment of a model for diabetic cardiorenal syndrome in female mRen2.Lewis

描述（由申请人提供）：糖尿病是美国死亡的主要原因之一，也是绝经前和绝经后妇女心血管（CV）和终末期肾脏疾病发展的公认独立危险因素。与年龄匹配的男性或非糖尿病女性相比，糖尿病女性表现出更大的心血管和肾脏疾病患病率。最近糖尿病患者心肾综合征的分类强调心脏和肾脏同时损伤和/或功能障碍的发生。重要的是，合并肾功能和心功能障碍或衰竭的糖尿病高血压妇女雌激素耗竭显著导致这些患者的预后不良。缺乏女性高血压糖尿病患者心肾综合征的体内实验模型限制了我们阐明该综合征的潜在机制以及开发更有效的治疗方法的能力。本应用程序旨在建立先天性mRen2糖尿病心肾综合征的实验模型。Lewis大鼠，这反映了在雌激素降低的糖尿病高血压妇女中心脏和肾脏功能障碍/衰竭共存。这些研究还将确定新型雌激素受体GPR30在减轻心肾综合征发生和进展中的作用，这可能揭示减少女性心血管疾病的新治疗方法。

DESCRIPTION (provided by applicant): 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.