Elsevier

Seminars in Nephrology

Volume 33, Issue 1, January 2013, Pages 44-53
Seminars in Nephrology

The Role of the Renin-Angiotensin-Aldosterone System in Obesity-Related Renal Diseases

https://doi.org/10.1016/j.semnephrol.2012.12.002Get rights and content

Summary

Obesity is an independent risk factor for the development and progression of chronic kidney disease and one of the emerging reasons for end-stage renal disease owing to its dramatic increase worldwide. Among the potential underlying pathophysiologic mechanisms, activation of the renin-angiotensin-aldosterone-system (RAAS) plays a central role. Increased angiotensin II (AngII) levels also are central in hypertension, dyslipidemia, and insulin resistance, which, taken together with obesity, represent the metabolic syndrome. Increased AngII levels contribute to hyperfiltration, glomerulomegaly, and subsequent focal glomerulosclerosis by altering renal hemodynamics via afferent arteriolar dilation, together with efferent renal arteriolar vasoconstriction as well as by its endocrine and paracrine properties linking the intrarenal and the systemic RAAS, adipose tissue dysfunction, as well as insulin resistance and hypertension. The imbalance between increased AngII levels and the angiotensin converting enzyme 2/Ang (1-7)/Mas receptor axis additionally contributes to renal injury in obesity and its concomitant metabolic disturbances. As shown in several large trials and experimental studies, treatment of obesity by weight loss is associated with an improvement of kidney disease because it also is beneficial in dyslipidemia, hypertension, and diabetes. The most promising data have been seen by RAAS blockade, pointing to the central position of RAAS within obesity, kidney disease, and the metabolic syndrome.

Section snippets

The RAAS

The RAAS is classically known for its role in the regulation of blood pressure, fluid, and electrolyte balance. In addition, it is involved in many physiologic and pathophysiologic processes such as tissue growth and hypertrophy, inflammation, and interference with glucose, lipid, and energy metabolism.13 RAAS blockade is highly effective in retarding the progression of renal disease in human beings and experimental animals.14

Angiotensinogen (AGT), the obligate precursor of all bioactive

Enhanced RAAS Activity in Adipose Tissue

In human adipose tissue and in primary cultured adipocytes, as well as in commonly used rodent models, expression of all components of the RAAS have been shown including AGT, ACE, renin, and AngII type 1 (AT1)- and type 2- (AT2) receptors.20 In elegant rodent models, AGT produced in adipose tissue contributes up to 30% of the systemic circulating AGT level.21 Mice whose AGT expression was restricted to adipose tissue have AGT circulating in the blood stream, are normotensive, and show restored

Local RAAS and the Kidney

In obesity, hyperfiltration and glomerular hypertrophy are observed in parallel to increasing body mass.45, 46 Because there is a fixed number of nephrons per kidney determined at birth, these changes lead to enhanced work for each single nephron associated with increased glomerular pressure, glomerular filtration rate, renal plasma flow, and increased filtration fraction. In a study of healthy normotensive human beings, examination of the baseline RAAS and the renal hemodynamic response to ACE

RAAS and Insulin Resistance

AngII as the major effector of RAAS. However, aldosterone are involved in the development of insulin resistance as a result of various pathways including influence on blood flow and sympathetic activation but also by direct influence on insulin metabolism. In the normal insulin pathway metabolic signaling is mediated through serine phosphorylation of specific insulin receptors in the muscle cell with release of nitric oxide (NO) and acetyl CoA carboxylase whereas proliferative signaling depends

RAAS and Dyslipidemia

The lipid nephrotoxicity hypothesis, proposed more than 3 decades ago, suggested that proteinuria, decreased albumin levels, and the resultant hyperlipidemia may cause a glomerulosclerosis similar to atherosclerosis.93 HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase) inhibitors seem to be effective in preventing the progression of chronic kidney disease as shown by a meta-analysis describing that effective treatment of dyslipidemia decreased proteinuria and retarded the

RAAS Blockade, Hypertension, Metabolic Syndrome, and Progression of Chronic Kidney Disease

Obesity and its subsequent metabolic changes are characterized by increased local RAAS in adipose tissue and increased intrarenal RAAS activity, both cross-talking with increased systemic RAAS activity. Hypertension attributable to obesity has been estimated to be approximately 80% for men and approximately 60% for women.111

In several clinical trials ACE inhibitors and angiotensin-receptor blockers have been shown to reduce cardiovascular and renal risk, and also to reduce the risk for

Conclusions

Obesity is an independent risk factor for the development and progression of chronic kidney disease and one of the emerging reasons for ESRD because of its dramatic increase worldwide. Among the potential underlying pathophysiologic multifactorial mechanisms, RAAS activation is likely a key player in this process. Increased AngII levels also are pivotal for the development of hypertension, dyslipidemia, and insulin resistance. Increased local and systemic AngII levels contribute to

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