N-methyl-D-aspartate receptors (NMDAr) participates in renal hemodynamic regulation and blood pressure homeostasis

点击翻译按钮获取中文摘要

Abstract Internationally, hypertension is the leading single risk factor for mortality. However, in more than 90% of hypertensive patients, the cause is unknown. There is a critical need to understand the mechanisms behind the origins of hypertension to enable the development of new therapies. Connecting tubule-glomerular feedback (CNTGF) is an epithelial sodium channel (ENaC)-dependent kidney feedback mechanism that facilitates sodium excretion under certain physiological situations by inducing vasodilation. It has been previously demonstrated that amino acids, mediated by the N-methyl-D-aspartate receptors (NMDAr), can induce renal vasodilation. The NMDAr-induced vasodilation mechanism is unknown. Dr. Romero’s long-term objectives are to explore the consequences of impaired vasodilation in the kidney as a cause of hypertension and develop a program to thoroughly understand some of the causes of human hypertension. The main hypothesis is that the mechanisms of NMDAr-mediated vasodilation and CNTGF are closely related and that impairments of these biological pathways induce hypertension. The hypothesis will be addressed through the following specific aims. AIM I: To determine the mechanism of NMDAr-induced renal vasodilation. We will evaluate the role of NMDAr in CNTGF-induced vasodilation in vitro using microperfusion, and in-vivo using NMDAr NR2C null mice. Aim II: To determine the mechanism by which NMDAr interacts with ENaC. Using tubule microperfusion, electrophysiology, confocal imaging techniques, and proteoteomic approaches, we will explore the molecular signaling associated with the interaction between NMDAr and ENaC which induces the vasodilation. Aim III: To test the effect of NMDAr on blood pressure and renal hemodynamics. We will evaluate the role of NMDA on blood pressure and renal hemodynamics by treating ENaC channel gain-in-function mice (Liddle syndrome) with NMDAr inhibitors. The objective and hypothesis of this proposal align with those of the NHLBI that promote the prevention and treatment of heart and blood diseases by stimulating basic discoveries about the causes of diseases. Dr. Romero’s development plan during these funding years include: 1) Increasing his research experience by consolidating the microperfusion technique and exploring two new areas relating to electrophysiology and proteomics while expanding his critical thinking and laboratory management skills; 2) Increasing his teaching and mentoring experience; 3) Further developing his communication skills and publication record. Dr. Romero will be guided by Dr. Wall as a principal mentor as well as Dr. Eaton and Dr. Hoover as a co-mentors. In addition, an advisory committee will be supporting the development of this plan. Dr. Romero’s career goal is to be an independently funded principal investigator in a highly ranked U.S. university to study renal hemodynamics and tubular transport interactions and their roles in hypertension. This career development plan will be performed entirely at Emory University, GA, USA.