Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms

Abstract

Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin-angiotensin-aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin-angiotensin-aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.

Keywords: blood pressure; chronic renal insufficiency; kidney; leptin; melanocortins; mineralocorticoids.

Figure 1

Effect of weight gain to shift the frequency distribution of blood pressure toward higher levels.

Figure 2

Summary of mechanisms by which obesity initiates development of hypertension and renal injury. Sympathetic nervous system (SNS); Renin–angiotensin–aldosterone system, RAAS; Mineralocorticoid receptor, MR; Proopiomelanocortin, POMC, neurons.

Figure 3

Kidneys from an obese dog fed a high fat diet for 8 weeks (A) and a severely obese (ob/ob) mouse with leptin deficiency (B). In obese dogs, the fat adheres tightly to the renal capsule, penetrates the renal capsule, and invades the renal sinuses. In obese mice the kidney is surrounded by fat but the fat does not adhere to the kidneys.

Figure 4

Changes (Δ) in mean arterial pressure (mmHg), cumulative sodium balance (mmol), and glomerular filtration rate (ml/min) in control, untreated dogs and mineralocorticoid receptor antagonist (eplerenone) treated dogs fed a high fat diet for 5 weeks to develop obesity. (Redrawn from data in reference 46).

Figure 5

Mean arterial pressure and heart rate responses to bilateral renal denervation in dogs with established obesity hypertension. Obesity was induced by feeding a high fat diet for 46 days prior to surgical denervation of both kidneys. Lean control values prior to beginning the high fat diet are shown by the open bars. (Data are from reference 62).

Figure 6

Leptin-melanocortin activation in distinct areas of the brain and through multiple intracellular signaling pathways may differentially regulate appetite, energy expenditure, and arterial pressure. Leptin binding to the leptin receptor (LepR) activates its associated JAK2 tyrosine kinase (Tyr), leading to the autophosphorylation of tyrosine residues on JAK2 and phosphorylation of Tyr985 and Tyr1138. Phosphorylation of Tyr985 activates SHP2/MAPK and phosphorylation of Tyr1183 activates STAT3, a transcription factor. STAT3 activation, in addition to mediating multiple effects of leptin, also induces transcription of SOCS3 which binds to phosphor-Tyr985 and to the LepR-JAK2 complex and has a feedback effect to attenuate LepR-mediated signaling. PTP1B attenuates leptin signaling by dephosphorylation of JAK2. LepR activation of proopiomelanocortin (POMC) neurons causes release α-melanocyte stimulating hormone (α-MSH) which stimulates melanocortin 4 receptors (MC4R) in second-order neurons of the hypothalamus, brainstem, and spinal cord intermediolateral nucleus (IML).

Figure 7

Possible interactions among leptin, sympathetic activity, endothelial dysfunction and nitric oxide (NO) synthesis, and negative regulators of leptin signaling, cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B), in obesity hypertension. The net effect of leptin on blood pressure depends on the degree of endothelial dysfunction and whether there is selective resistance to the weight loss effects of leptin with preservation of the sympathetic effects of leptin in obesity.