PPARs in the Renal Regulation of Systemic Blood Pressure

de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

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“…343). Thus, enalapril upregulates PPAR-␣ and PPAR-␥ and displays antiatherogenic and anti-inflammatory effects in mice (90).…”

Section: The Sirtuin-ras Connectionmentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…PPAR agonists can attenuate the adverse effects of Ang II by downregulating Ang II concentration and ACE and AT1R gene expression [6]. This is the first study to verify the upregulation of ACE2 by PPAR agonists in all insulin-sensitive tissues.…”

Section: Discussionmentioning

confidence: 74%

“…HFD-induced elevation in FFA activates PPAR [19], which subsequently regulates RAS [6]. Additionally, the upregulation of hepatic ACE2 expression may result from the NASHrelated fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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1312 Pioglitazone Upregulates Angiotensin Converting Enzyme 2 Expression in Insulin-Sensitive Tissues in Rats With High Fat Diet-Induced Non-Alcoholic Steatohepatitis

Zhang¹,

Xu²,

Liu³

et al. 2013

Journal of Hepatology

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Background and Aim. Thiazolidinediones (TZDs) can improve hepatic steatosis in nonalcoholic steatohepatitis (NASH). Angiotensin (Ang) II, the primary effector of renin-angiotensin system (RAS), plays vital roles in the development and progression of NASH. And some AngII-mediated effects can be regulated by TZDs. Angiotensin-converting enzyme (ACE) 2, a new component of RAS, can degrade Ang II to attenuate its subsequent physiological actions. We aimed to evaluate the effects of TZDs on ACE2 expression in insulin-sensitive tissues in NASH rats. Methods. Forty rats were divided into the normal control, high-fat diet (HFD), pioglitazone control, and HFD plus pioglitazone groups. After 24 weeks of treatment, we evaluated changes in liver histology and tissue-specific ACE2 expression. Results. ACE2 gene and protein expression was significantly greater in liver and adipose tissue in the HFD group compared with normal control group, while was significantly reduced in skeletal muscle. Pioglitazone significantly reduced the degree of hepatic steatosis compared with the HFD group. Pioglitazone significantly increased ACE2 protein expression in liver, adipose tissue, and skeletal muscle compared with the HFD group. Conclusions. Pioglitazone improves hepatic steatosis in the rats with HFD-induced NASH and upregulates ACE2 expression in insulin-sensitive tissues.

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“…It also has a well-recognized role in regulating multiple metabolic processes. PPARγ can regulate BP by modulation of the renin angiotensin aldosterone system (RAAS), which is an important pathway in managing systemic BP and interstitial fluid volume (Roszer and Ricote, 2010). In transgenic and knockout mice studies with mutant PPARγ, it has been demonstrated that quantitative variants causing decreased PPARγ expression are potential contributors to EH (Halabi et al, 2008;Tsai et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Association of SNPs in the PPARγ gene and hypertension in a Mongolian population

Yang¹,

Rg²,

Py³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The association of single nucleotide polymorphisms (SNPs) in PPARγ with hypertension is controversial. The aim of the present study was to clarify the contributions of PPARγ genetic variants to hypertension through an association study. A total of 414 unrelated Mongolian herdsmen and 524 Han farmers were included in this study. Fourteen intronic SNPs were analyzed and genotyped using a polymerase chain reaction/ligase detection reaction assay. Prior to correction for multiple testing, the SNPs rs6802898 and rs12633551 were significantly associated with the prevalence of hypertension in the Han and Mongolian populations, respectively. The genetic association of each SNP with hypertension was individually tested using logistic regression. The SNP rs6802898 was associated with hypertension in both dominant (P = 0.033) and additive models (P = 0.026) in the Han population, whereas the SNP rs12633551 was associated with hypertension in both dominant (P = 0.014) and additive models (P = 0.0073) in the Mongolian population. Moreover, SNP rs12633551 had a significant effect on systolic and diastolic blood pressure response. However, none of these associations were statistically significant after Bonferroni correction for multiple testing, although there was a significant difference among the haplotypes in the Han and Mongolian populations. Interestingly, there was an association of the PPARγ haplotypes with hypertension even after 19295-19308 (2015) Bonferroni correction. Thus, determination of the PPARγ haplotypes in different populations may prove informative for assessment of the genetic risk for hypertension.

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PPARs in the Renal Regulation of Systemic Blood Pressure

Cited by 36 publications

References 88 publications

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

1312 Pioglitazone Upregulates Angiotensin Converting Enzyme 2 Expression in Insulin-Sensitive Tissues in Rats With High Fat Diet-Induced Non-Alcoholic Steatohepatitis

Association of SNPs in the PPARγ gene and hypertension in a Mongolian population

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