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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.

Key points

  • Obesity is associated with chronic diseases, including hypertension, which is a major risk factor for chronic kidney disease and cardiovascular diseases such as stroke, myocardial infarction and heart failure.

  • Excessive weight gain, especially when associated with visceral obesity, raises blood pressure and is the most important known risk factor for primary (essential) hypertension.

  • Abnormal kidney function, which is associated with increased tubular sodium reabsorption, has a key role in initiating obesity-associated hypertension.

  • Mechanisms that initiate obesity-induced sodium retention include kidney compression by visceral, perirenal and renal sinus fat, stimulation of the renin–angiotensin–aldosterone system, aldosterone-independent mineralocorticoid receptor activation and activation of the sympathetic nervous system.

  • Sympathetic activation in obesity may be mediated by hypoxia, chemoreceptor activation, baroreflex dysfunction and adipokines, including leptin, which activates the central nervous system melanocortin pathway.

  • Chronic obesity may gradually amplify hypertension, resulting in resistance to antihypertensive treatment and initiating a pathophysiological cascade of factors that exacerbate target organ injury.

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Fig. 1: Obesity shifts the frequency distribution of blood pressure.
Fig. 2: Potential effects of kidney compression on renal haemodynamics, sodium reabsorption and renin secretion.
Fig. 3: Mechanisms of obesity-induced hypertension, renal injury and cardiovascular disease.
Fig. 4: Potential mechanisms and consequences of MR activation in obesity.
Fig. 5: Effects of CNS leptin–melanocortin activation on blood pressure and metabolic functions.
Fig. 6: Obesity-induced hypertension and the effects of renal denervation.
Fig. 7: Potential mechanisms of SNS activation in obesity.

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Acknowledgements

The authors’ research was supported by grants from the US National Heart, Lung, and Blood Institute (P01 HL51971), the US National Institute of General Medical Sciences (P20 GM104357 and U54 GM115428) and the US National Institute of Diabetes and Digestive and Kidney Diseases (1K08DK099415-01A1) of the US National Institutes of Health.

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Nature Reviews Nephrology thanks the anonymous reviewers for their contribution to the peer review of this work.

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J.E.H. wrote the manuscript. All authors researched the data for the article, contributed to discussions of the content and reviewed or edited the manuscript before submission.

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Glossary

Lipotoxicity

The toxic effect of lipids that accumulate in non-adipose tissue and cause cellular dysfunction.

Renal sinus fat

(RSF). The adipose tissue that accumulates in the renal sinuses, which are cavities within the kidneys that are occupied by the renal pelvis, renal calyces, blood vessels and nerves.

Perirenal fat

(PRF). Also called the adipose capsule of the kidney. The perirenal fat is a structure located between the renal fascia and renal capsule.

Blood flow reserve

The maximum increase in blood flow above the resting level of blood flow.

Hypoxaemia

The condition of abnormally low oxygen concentration in the blood.

Baroreflex

Often called the baroreceptor reflex. The reflex mechanism by which stretch receptors (baroreceptors), located especially in the carotid sinuses and aortic arch, regulate blood pressure.

Hypercapnia

The condition of excessive carbon dioxide concentration in the blood.

Eucapnic

The condition of having normal carbon dioxide concentration in the blood.

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Hall, J.E., do Carmo, J.M., da Silva, A.A. et al. Obesity, kidney dysfunction and hypertension: mechanistic links. Nat Rev Nephrol 15, 367–385 (2019). https://doi.org/10.1038/s41581-019-0145-4

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