Career Plan: This proposal is designed for the dual purpose of advancing knowledge of kidney physiology while preparing myself for an independent research career as a physician scientist. My current focus is on factors contributing to the regulation of kidney oxygen consumption with the long term goal to develop a comprehensive kidney wide model for the control of kidney metabolism. A five year career development plan is proposed which will allow didatics and informal instruction in research techniques, biostatistics, manuscript preparation and research ethics with the ultimate goal of an independent research career. Research Plan: The first hypothesis is that nitric oxide (NO), Angiotensin II (Ang II) and renal alpha2- adenergic nerves (RSN) interact in regulation of kidney oxygen consumption. We base this hypothesis on the known interactions NO, Ang II and RSN have in regulation of renal hemodynamics and transport functions and on the observations by our lab that NO, derived from the NOS-1 isoform, reduces kidney oxygen consumption per sodium ion reabsorbed (QO2/TNa). In addition, preliminary observations by others have noted a role for Ang II and RSN in effecting renal oxygen consumption (Q02). An additional hypothesis, to be tested in the later years of the proposal period, is that alterations in renal O2 uptake reflect changes in energy requirements not only for transport functions, as traditionally been studied, but also non-transport functions such as gluconeogenesis. This is based on the observation that the kidney performs other functions that require energy, such as gluconeogenesis.
The specific aims are to 1) Define the site(s) along the nephron and location within the cell where events occur that render QO2 and QO2/TNa sensitive to NO, 2) Determine how the pool of NO that affects QO2 is regulated within the nephron, with specific attention toward Ang II and RSN, 3) Determine whether, and by what mechanism(s), kidney oxygen content is stabilized by tradeoffs between tubular reabsorption and GNG which are the principle users of energy in the kidney. Relevance: Understanding factors which regulate kidney oxygen consumption may help identify patients at risk of acute kidney injury due to renal ischemia and may identify neurohormonal contributions to the progression of chronic kidney disease.
|Rifkin, Dena E; Abdelmalek, Joseph A; Miracle, Cynthia M et al. (2013) Linking clinic and home: a randomized, controlled clinical effectiveness trial of real-time, wireless blood pressure monitoring for older patients with kidney disease and hypertension. Blood Press Monit 18:8-15|
|Miracle, Cynthia M; Rieg, Timo; Mansoury, Hadi et al. (2008) Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt. Am J Physiol Renal Physiol 295:F995-F1002|