Renin–angiotensin system, natriuretic peptides, obesity, metabolic syndrome, and hypertension: an integrated view in humans

Sarzani, Riccardo; Salvi, F.; Dessı̀-Fulgheri, Paolo; Rappelli, A

doi:10.1097/hjh.0b013e3282f624a0

Cited by 255 publications

(208 citation statements)

References 166 publications

(248 reference statements)

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“…15 Aliskiren may therefore offer treatment benefits compared with ARBs for BP reduction in patients with hypertension and metabolic syndrome or obesity-perhaps because of its distribution to adipose tissue, as adipocytes may contribute to BP elevation in obesity-related hypertension through the generation of Ang II. 5,25 More studies are required to investigate further the effects of aliskiren in patients with hypertension and metabolic disorders.…”

Section: Discussionmentioning

confidence: 99%

Comparative efficacy and safety of aliskiren and irbesartan in patients with hypertension and metabolic syndrome

Krone

Hanefeld

Hf³

et al. 2010

J Hum Hypertens

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Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/ 7.1 mm Hg after 12 weeks, significantly greater (Pp0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to o135/85 mm Hg (29.2 vs 16.7% with irbesartan; P ¼ 0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both Po0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome.

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Section: Discussionmentioning

confidence: 99%

Comparative efficacy and safety of aliskiren and irbesartan in patients with hypertension and metabolic syndrome

Krone

Hanefeld

Hf³

et al. 2010

J Hum Hypertens

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“…The evidence that adipocytes can produce substantial amounts of AGT has supported the concept that increased adiposity can significantly contribute to inappropriately normal or even elevated plasma renin activity. 25,26 Ang II itself, through type 1 receptors (AT1), was proposed as a trophic factor in adipose tissue growth and development; 27 indeed, Ang II stimulates lipogenesis 28 and pre-adipocyte differentiation. 29 Some limitations of this study should be taken into account.…”

Section: Discussionmentioning

confidence: 99%

Angiotensinogen promoter variants influence gene expression in human kidney and visceral adipose tissue

et al. 2009

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Human angiotensinogen (AGT) gene promoter polymorphisms (GÀ217A; AÀ20C; GÀ6A) influence AGT transcription in vitro and have been implicated in the genetics of essential hypertension. We analysed the association among AGT promoter variants and AGT mRNA levels in human kidney and visceral adipose tissue (VAT) in vivo. Samples of kidney and VAT were obtained from 35 consecutive patients undergoing renal surgery. The AGT gene promoter of each patient was sequenced to identify variants. AGT gene expression was studied by real-time PCR TaqMan assay. Clinical data obtained before surgery were also considered in the statistical analysis. Two new polymorphisms at À175 and at À163 were identified. Although AGT expression was significantly higher in VAT than in the kidney, when both variants were present together AGT expression in VAT was about fivefold lower (P ¼ 0.033) than in the wild haplotype. This lower AGT expression in VAT suggests that the proximity and linkage of À175A and À163A variants might destabilize the binding of specific transcription factors to an acute-phase responsive element 3. Among the known AGT promoter variants, only À20C SNP has an important effect on tissue-specific differential AGT expression in the human tissues studied, inducing a 3.8-fold increase in AGT mRNA localized only in the kidney medulla (P ¼ 0.038). The other known polymorphisms (GÀ6A; GÀ217A) were not associated with different levels of AGT expression. Our results support the hypothesis that some human AGT promoter variants influence transcriptional activity in a tissue-specific way in humans.

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“…Besides nutritional and metabolic factors, hemodynamic alterations, and vascular dysfunction are believed to play a role (Mather et al 2013). Vasomotor peptide systems, especially the renin-angiotensin and kallikrein-kinin systems (KKS), have been suggested to be involved in the development of insulin resistance (Mayfield et al 1996, Sarzani et al 2008, a hypothesis that has been recently supported by the results of clinical trials.…”

Section: Introductionmentioning

confidence: 83%

Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man

Potier¹,

Waeckel²,

Fumeron³

et al. 2014

Journal of Endocrinology

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The kallikrein-kinin system has been suggested to participate in the control of glucose metabolism. Its role and the role of angiotensin-I-converting enzyme, a major kinininactivating enzyme, are however the subject of debate. We have evaluated the consequence of deficiency in tissue kallikrein (TK), the main kinin-forming enzyme, on the development of insulin resistance and diabetes in mice and man. Mice with inactivation of the TK gene were fed a high-fat diet (HFD) for 3 months, or crossed with obese, leptindeficient (ob/ob) mice to generate double ob/ob-TK-deficient mutants. In man, a loss-offunction polymorphism of the TK gene (R53H) was studied in a large general population cohort tested for insulin resistance, the DESIR study (4843 participants, 9 year follow-up). Mice deficient in TK gained less weight on the HFD than their WT littermates. Fasting glucose level was increased and responses to glucose (GTT) and insulin (ITT) tolerance tests were altered at 10 and 16 weeks on the HFD compared with standard on the diet, but TK deficiency had no influence on these parameters. Likewise, ob-TK K/K mice had similar GTT and ITT responses to those of ob-TK C/C mice. TK deficiency had no effect on blood pressure in either model. In humans, changes over time in BMI, fasting plasma glucose, insulinemia, and blood pressure were not influenced by the defective 53H-coding TK allele. The incidence of diabetes was not influenced by this allele. These data do not support a role for the TK-kinin system, protective or deleterious, in the development of insulin resistance and diabetes.

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Renin–angiotensin system, natriuretic peptides, obesity, metabolic syndrome, and hypertension: an integrated view in humans

Cited by 255 publications

References 166 publications

Comparative efficacy and safety of aliskiren and irbesartan in patients with hypertension and metabolic syndrome

Comparative efficacy and safety of aliskiren and irbesartan in patients with hypertension and metabolic syndrome

Angiotensinogen promoter variants influence gene expression in human kidney and visceral adipose tissue

Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man

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