The renin-angiotensin system in obesity hypertension.

Abstract

JRAAS 2001;2 (suppl 1):S114-S119 Introduction Increased intra-abdominal fat tissue is an important risk factor for hypertension. Development of hypertension in obese individuals is associated with increases in blood volume, heart rate, cardiac output, and cardiac mass. Frequently discussed pathogenic mechanisms involved in the development of ‘obesity hypertension’ include insulin resistance, increased sympathetic nervous system activity, and changes in sodium balance. Obesity-related changes in kidney function include increased renal blood flow and glomerular filtration rate, but also increased tubular sodium reabsorption, leading to a rightward shift of the pressure-natriuresis curve. Intrarenal pressure is significantly increased in obesity, probably by accumulation of intrarenal fat and extracellular matrix. Sympathetic nerve activity to the kidneys is also enhanced in obesity, with renal norepinephrine spill-over being twice that of lean individuals. One of the driving forces for sympathetic stimulation appears to be directly related to the central action of the adipose tissue-derived hormone, leptin. Bilaterally renal-denervated animals do not develop hypertension or sodium retention despite weight gain under a high-fat diet, further illustrating the role of sympathetic renal innervation in obesity-related sodium retention. The humoral control of sodium balance involves both aldosterone and atrial natriuretic peptide (ANP). As discussed below, aldosterone plasma levels are increased in obesity. Furthermore, ANP plasma levels are decreased and the ANP response to a sodium load is significantly blunted in obese subjects. Both findings can potentially contribute to obesity-associated sodium retention. Expression of the ANP clearance receptor (NPrC) gene is increased in human adipose tissue of obese hypertensive subjects, but not obese normotensive subjects. In rats, fasting selectively inhibits adipose tissue NPr-C gene expression and increases circulating ANP levels. These findings suggest that increased expression of the NPr-C receptor gene in adipose tissue may directly influence the systemic availability and thus action of natriuretic peptides in obese individuals. Furthermore, the response to exogenous ANP (blood pressure (BP) reduction and natriuresis) in obese hypertensive individuals is significantly enhanced at the end of a low-calorie diet. Thus, increased expression of NPr-C in adipose tissue may counteract the protective effects of natriuretic peptides and promote the development of obesity hypertension. Furthermore, down-regulation of the adipocyte NPr-C receptor during weight reduction or fasting might explain the natriuresis observed during the initial phase of a hypocaloric diet.