Obesity, kidney dysfunction and hypertension: mechanistic links

Abstract

Excessive adiposity raises blood pressure and accounts for 65-75% of primary hypertension, which is a major driver of cardiovascular and kidney diseases. In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension, which is often mild before the development of target organ injury. Factors that contribute to increased sodium reabsorption in obesity include kidney compression by visceral, perirenal and renal sinus fat; increased renal sympathetic nerve activity (RSNA); increased levels of anti-natriuretic hormones, such as angiotensin II and aldosterone; and adipokines, particularly leptin. The renal and neurohormonal pathways of obesity and hypertension are intertwined. For example, leptin increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway, and kidney compression and RSNA contribute to renin-angiotensin-aldosterone system activation. Glucocorticoids and/or oxidative stress may also contribute to mineralocorticoid receptor activation in obesity. Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension. Patient management therefore often requires multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes and inflammation. If more effective strategies for the prevention and control of obesity are not developed, cardiorenal, metabolic and other obesity-associated diseases could overwhelm health-care systems in the future.

Fig. 1 |. Obesity shifts the frequency distribution of blood pressure.

Not all individuals who are obese have blood pressures in the hypertensive range (>140/90 mmHg); however, obesity raises blood pressure above the baseline level for an individual (for example, from point A to B). Conversely, weight loss lowers blood pressure in individuals who are obese but considered to be normotensive (for example, from point B to A) as well as in those who are obese and hypertensive. Increasing duration of obesity exacerbates the obesity-induced shift of the blood pressure frequency distribution to higher levels of blood pressure.

Fig. 2 |. Potential effects of kidney compression on renal haemodynamics, sodium reabsorption and renin secretion.

(1) Increased volumes of renal sinus fat and perirenal fat (not shown) due to obesity might result in compression of the thin loop of Henle and vasa recta of the renal medulla. (2) Such compression would initially result in a reduction in tubular flow rate, increased fractional NaCl reabsorption in the nephron, including in the thick loop of Henle, and (3) a reduction in NaCl concentration at the macula densa cells in the early distal tubule. (4) The reduction in NaCl concentration would, in turn, cause a macula densa feedback-mediated dilation of afferent arterioles, increases in renal blood flow and glomerular filtration rate (GFR) and stimulation of renin secretion from the juxtaglomerular cells of the afferent arterioles.

Fig. 3 |. Mechanisms of obesity-induced hypertension, renal injury and cardiovascular disease.

Metabolic abnormalities in individuals with obesity may interact synergistically with hypertension to cause renal injury and cardiovascular disease. Increased sympathetic nervous system (SNS) activity stimulates renal tubular sodium reabsorption directly and indirectly by stimulating the release of renin, which activates the renin-angiotensin-aldosterone system (RAAS). Kidney compression may also increase sodium reabsorption in the loop of Henle and contribute to increased renin release and RAAS activation. Activation of the RAAS leads to increased formation of angiotensin II and aldosterone, which both stimulate renal tubular sodium reabsorption. Aldosterone-independent mechanisms may also contribute to renal tubular mineralocorticoid receptor (MR) activation and increased sodium reabsorption. The increased renal sodium reabsorption leads to compensatory renal vasodilation which, in combination with increased blood pressure, initially causes increased glomerular hydrostatic pressure and glomerular hyperfiltration, which may further exacerbate renal injury. As obesity is sustained over many years, progressive renal injury can exacerbate hypertension and lead to resistance to antihypertensive therapies.

Fig. 4 |. Potential mechanisms and consequences of MR activation in obesity.

Under normal conditions, aldosterone is the primary agonist of the renal tubular mineralocorticoid receptor (MR). Obesity leads to increases in renin secretion and the formation of angiotensin II, which stimulates secretion of aldosterone from the adrenal gland. Leptin has also been suggested to stimulate aldosterone secretion in individuals with obesity. However, obesity might also lead to MR activation via aldosterone-independent mechanisms such as increased renal tubular expression of Racl and increased reactive oxygen species (ROS). Obesity might also enable cortisol-induced activation of the MR by inducing downregulation of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), which converts cortisol to cortisone. In contrast to cortisone, cortisol does not avidly bind the MR. Activation of the MR increases sodium reabsorption in the renal tubules, contributing to expansion of extracellular fluid volume and increased blood pressure in obesity.

Fig. 5 |. Effects of CNS leptin-melanocortin activation on blood pressure and metabolic functions.

Activation of leptin receptors (LepRs) in different neuronal populations and the resulting activation of three primary intracellular signalling pathways likely contribute to the differential effects of leptin on cardiometabolic functions in obesity, a | Activation of LepRs expressed on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC), nucleus tractus solitarius (NTS) of the brainstem and intermediolateral nucleus (IML) of the spinal cord causes release of a-melanocyte-stimulating hormone (aMSH), which stimulates melanocortin 4 receptors (MC4Rs) in second-order neurons of the hypothalamus, brainstem and spinal cord IML. b | Binding of leptin to the LepR activates its associated Janus tyrosine kinase 2 (JAK2) tyrosine kinase, leading to autophosphorylation of tyrosine residues on JAK2 and phosphorylation of Tyr985 and Tyr1138 on the LepR. Autophosphorylation of JAK2 activates insulin receptor substrate 2 (IRS2)-phosphatidylinositol 3-kinase (PI3K) signalling, which contributes to the blood pressure effects of leptin. Phosphorylation of Tyr985 activates Src homology 2 tyrosine phosphatase (SHP2)-mitogen-activated protein kinase (MAPK) signalling, which has an important role in the cardiometabolic actions of leptin. Phosphorylation of Tyr1138 activates signal transducer and activator of transcription 3 (STAT3). In addition to mediating multiple effects of leptin such as reduced food intake and increased blood pressure, STAT3 activation induces transcription of suppressor of cytokine signalling 3 (SOCS3), which binds to phospho-Tyr985 and to the LepR-JAK2 complex and attenuates LepR-mediated signalling. Protein tyrosine phosphatase 1B(PTP1B) also attenuates leptin signalling by dephosphorylating JAK2. CNS, central nervous system; DMV, dorsal motor nucleus of the vagus; PVN, paraventricular nucleus; RSNA, renal sympathetic nerve activity; RVLM, rostral ventrolateral medulla.

Fig. 6 |. Obesity-induced hypertension and the effects of renal denervation.

During days 4–31, obesity and associated hypertension were induced by feeding dogs supplements of cooked beef fat along with a fixed amount of a prescription diet. During this time, body weight increased by −50%. After day 31, dietary fat supplements were minimal and there were no further changes in body weight during the remainder of the study Chronic baroreflex activation (by electrical stimulation of the carotid sinuses) or bilateral surgical renal denervation normalized blood pressure in dogs with established obesity Values are means ± s.e. from 24-hour recordings of arterial pressure. Adapted with permission from REF., American Physiological Society

Fig. 7 |. Potential mechanisms of SNS activation in obesity.

As adipocytes grow larger, they secrete increased amounts of leptin, which increases sympathetic nervous system (SNS) activity mainly by stimulating proopiomelanocortin (POMC) neurons. These neurons release a-melanocyte-stimulating hormone, which stimulates melanocortin 4 receptors (MC4Rs) in the hypothalamus and brainstem. Leptin may also enhance the sensitivity of chemoreceptors to hypoxaemia. Obesity may also stimulate SNS activity via hypoxaemia, hypercapnia and chemoreceptor activation secondary to obstructive sleep apnoea and via other mechanisms that are still poorly defined. Obesity is also associated with rapid onset of baroreceptor dysfunction, but the mediators have not yet been elucidated. MSNA, muscle sympathetic nervous system activity; RSNA, renal sympathetic nerve activity.