DESCRIPTION (provided by applicant): Increased renal sinus fat (RSF) in humans is associated with hypertension and renal insufficiency. Obese animals have increased RSF that is associated with marked increases in renal interstitial pressures, suggesting a compressive force on the kidneys. This compression may slow flow in the renal tubules and thereby increase sodium reabsorption, especially in the loop of Henle located in the renal medulla. Consistent with this hypothesis is the finding that obesity results in sodium retention due to increased renal sodium reabsorption and compensatory glomerular hyperfiltration. However, the mechanisms responsible for increased sodium reabsorption are not fully understood, especially in humans. Elucidating the mechanisms and site of these pathological changes will provide a rational approach to developing prevention and treatment strategies for obesity-induced hypertension and renal injury. We propose to use novel magnetic resonance (MR) imaging techniques to evaluate RSF and renal medullary oxygenation in 25 obese hypertensive compared to 25 non-obese hypertensive, 25 obese non-hypertensive, and 25 non-obese non-hypertensive humans. Blood Oxygen Level Dependent (BOLD) MR is a non-invasive imaging technique that can detect levels of tissue oxygenation in humans. To assess the relationship between RSF and sodium reabsorption in the renal medulla, we will measure oxygenation in the renal medulla with BOLD imaging before and after furosemide which inhibits loop of Henle sodium chloride reabsorption. We hypothesize that administration of furosemide will result in greater inhibition of renal medullary sodium reabsorption thereby decreasing oxygen consumption and causing greater BOLD signal increases in obese hypertensives with more RSF than in normal weight hypertensives and non-obese non-hypertensives controls. Although obesity-hypertension is associated with activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, it remains unclear if these changes are linked to RSF accumulation. Therefore, we will also evaluate plasma renin and aldosterone levels and urinary catecholamines to determine their relationships to RSF. To accomplish these aims, the principal investigator will work with a multidisciplinary team including leaders in the fields of renal physiology and obesity-hypertension, clinical nephrology, and cardiovascular/renal imaging. This research will provide the investigator with the necessary tools to translate basic pathophysiologic mechanisms into potential prevention and treatment strategies for a complex and prevalent, clinical disorder. The proposed research will also facilitate the development of the investigator as an independent physician scientist and the data derived from these experiments will be used to apply for R01 funding.

PUBLIC HEALTH RELEVANCE: Obesity is a major health concern and recent estimates indicate that over 78 million Americans are obese. Visceral obesity, and specifically increased renal sinus fat, is now recognized as an independent contributor to hypertension and renal disease. However, the mechanisms by which specific fat depots contribute to these disorders are not fully understood. The proposed studies will use state-of-the-art imaging methods in obese humans to determine the mechanisms that link increased renal sinus fat to kidney dysfunction and hypertension. These studies may also provide a new diagnostic tool as well as improved strategies for treating obesity associated hypertension and renal injury.