An estimated 15% of U.S. adults are estimated to have chronic kidney disease (CKD), with cardiovascular disease (CVD) the greatest cause of death in this population. Metabolic acidosis is common in CKD, and has deleterious effects on both the kidney and the heart. Complicating our understanding and limiting our ability to prevent these effects are gaps in our knowledge of the integrated cardiorenal response to acidosis, which is largely influenced by cellular level acid-base transporters. The Na+/HCO3- co-transporter (NBCe1-B) is one such transporter. There is accumulating evidence that NBCe1-B is involved in the renal response to acidosis and the pathophysiologic development of cardiac hypertrophy, but the consequence of NBCe1-B loss on these systems has never been tested at the whole animal level. The goal of this project is to determine the role of NBCe1-B in the kidney and heart by comparing the renal and cardiac phenotypes of wild-type (WT) and NBCe1-B knockout (KO) mice. The over-arching hypothesis of this proposal is that NBCe1-B is essential for renal (Aim 1) and cardiac (Aim 2) acid-base handling. The purpose of Aim 1 is to determine the abundance, distribution, and function of NBCe1-B in the WT mouse kidney during acid-challenged conditions. This work will include a series of western-blot and fluorescent immunohistochemistry experiments as well as a comparison of renal acid-base handling during acidosis in WT and NBCe1-B KO mice as assessed by blood-gas parameters, ammonia excretion, and titratable acid excretion. The purpose of Aim 2 is to determine the exact type and mechanism of cardiac impairment in NBCe1-B-KO mice. The mice will receive a cardiac work-up similar to patients with heart- failure, incorporating electrocardiogram, echocardiogram, and left-ventricular pressure catheterization measurements. Cellular level investigation of cardiomyocytes will include histological analysis, molecular assessment for evidence of pro-hypertrophic mechanisms using Western blot and RT-qPCR, and evaluation of Ca2+ handling in isolated cardiomyocytes using Ca2+ sensitive microscopy. The experiments outlined in this proposal will determine the role of NBCe1-B in the renal and cardiac systems, providing insights into the cardiorenal response to acidosis. This work will take place at the University at Buffalo, Jacobs School of Medicine and Biomedical Sciences (JSMBS), in the laboratory of Dr. Mark Parker, who is an expert in ion transport and pH regulation. The training plan is tailored for development as a physician-scientist in the field of nephrology, and will include clinical preceptorships in nephrology and cardiology in order to gain cross-disciplinary experience, reflecting the research goals of this proposal. These longitudinal clinical preceptorships will be with successful physician-scientists, who will also be directly involved in the proposed research, thereby providing integrated mentorship over the course of the fellowship.
Metabolic acidosis is common in chronic kidney disease (CKD), and contributes to progression of kidney disease and the development of cardiovascular disease; the latter of which is the leading cause of mortality in patients with CKD. This project aims to understand the impact of cellular level acid-base transport on the cardiorenal response to acidosis. Since renal and cardiac outcomes in CKD are intertwined, this project has immediate impact on the understanding of CKD pathophysiology.
