Mitochondria-Mediated Effects and Therapeutic Potential of Atrial Natriuretic Peptide in Salt-Sensitive Hypertension Diversity Supplement

项目总结

PROJECT SUMMARY There is no specific treatment available for the subpopulation of patients with salt sensitivity of blood pressure (BP); unfortunately, the molecular mechanisms underlying salt-sensitivity remain poorly understood. One of the major proposed mechanisms for the development of salt-sensitive (SS) hypertension involves a defect in the ability of the kidneys to excrete salt. Atrial Natriuretic Peptide (ANP) encoded by Nppa, is a hormone known to promote salt excretion and BP reduction. There are clinical data implicating inherently low levels of ANP in the development of SS hypertension. Among other effects, ANP (via cGMP-related mechanisms) is known to be beneficial for mitochondrial bioenergetics and biogenesis. However, there is a gap in knowledge regarding the effects of ANP on mitochondria in the kidney, especially in SS hypertension. Our overarching hypothesis of the parent project is that in SS hypertension ANP deficiency/reduced sensitivity to ANP is causative to renal mitochondrial dysfunction and associated sodium transport imbalance. To address the central hypothesis of the parent proposal, we developed three specific aims: Aim 1. Establish whether increased ANP levels are beneficial for renal salt handling and cardiac function in SS hypertension. Aim 2. Determine whether low renal cGMP level resulting from lack of ANP causes an increase in renal mitochondrial Ca2+ and reactive oxygen species (ROS). Aim 3. Test the hypothesis that disrupted Ca2+ balance and excessive ROS production by dysfunctional mitochondria affect renal sodium handling in SS hypertension. From these proposed aims Dr. Spires and Dr. Ilatovskaya derived additional aims focused on studying the effects of ANP in SS hypertension in the context of glomerular function and injury specifically. For the focus of this supplemental project the aims are as follows: Suppl. Aim 1. To determine the physiological effects of ANP on glomerular function and injury in SS hypertension. Suppl. Aim 2. To analyze the effects of Nppa knockout on podocyte calcium handling and mitochondrial function in SS hypertension. Dr. Spires and Dr. Ilatovskaya put together a very strong team of mentors and collaborators to aid in completion of these Aims, and the methodological training of Dr. Spires during the Supplement will be combined with a rigorous career development program. The successful completion of the proposed studies in the parent proposal as well as the those proposed for this supplemental award will unravel the novel cause-effect mechanisms of salt-sensitivity.