A Clinical Link Between Peroxisome Proliferator-Activated Receptor γ and the Renin–Angiotensin System

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 33, No. 4A Clinical Link Between Peroxisome Proliferator-Activated Receptor γ and the Renin–Angiotensin System Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBA Clinical Link Between Peroxisome Proliferator-Activated Receptor γ and the Renin–Angiotensin System Curt D. Sigmund Curt D. SigmundCurt D. Sigmund From the Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA (C.D.S.). Search for more papers by this author Originally published1 Apr 2013https://doi.org/10.1161/ATVBAHA.112.301125Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:676–678A mechanistic link between peroxisome proliferator-activated receptor γ (PPARγ) and the renin–angiotensin system (RAS) has been previously proposed, but clinical evidence supporting the relationship is incomplete. In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Caron-Debarle et al show that 4 patients with familial partial lipodystrophy associated with early-onset severe hypertension carry mutations in PPARγ that impair its ability to act as a ligand-activated transcription factor. Cells isolated from these patients, and cells transfected with the same mutations in PPARγ, exhibit activation of the cellular RAS, increased production of reactive oxygen species (ROS), and markers of inflammation, all of which are dependent on the angiotensin-II (Ang-II) AT1 receptor (AT1R). This translational study further supports a role for PPARγ as a regulator of blood pressure through its ability to modulate the RAS.See accompanying article on page 829PPARγ is a ligand-activated transcription factor and target of the thiazolidinedione (TZD) class of antidiabetes mellitus medications. PPARγ is best recognized for its role in adipogenesis, but is also a regulator of systemic metabolism as evidenced by the pleiotropic abnormalities (lipodystrophy, insulin-resistance, and metabolic syndrome) caused by PPARγ mutations.1–3 Clinical studies of TZD use in type 2 diabetes mellitus, including the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial, documented improved endothelial function and modest, but significant reductions in blood pressure.4 Some of the same mutations that cause lipodystrophy and diabetes mellitus also cause severe hypertension and preeclampsia in human patients3 and in knock-in mice.5,6 Evidence suggests that PPARγ activity in the vascular endothelium and smooth muscle are important regulators of endothelial function, smooth muscle contraction, and systemic blood pressure.7,8Data suggesting a role for PPARγ in regulating blood pressure led many to search for downstream mediators. Early studies suggested that activation of PPARγ might antagonize the RAS by inhibiting expression of the Ang-II AT1R in vascular smooth muscle cells.9 PPARγ may also regulate expression of the renin and angiotensinogen (AGT) genes.10,11 TZD administration to Ang-II–treated Sprague–Dawley rats blunts the development of hypertension, endothelial dysfunction, and the induction of proinflammatory mediators.12 Similarly, TZD treatment of hypertensive transgenic mice overexpressing the renin and AGT genes improved endothelial function and lowered arterial pressure.13 An association between PPARγ and the RAS was also suggested by Tsai et al5 (and reviewed in Reference 14), who reported that mice carrying a mutant PPARγ allele equivalent to the mutation that causes hypertension in humans, exhibited increased blood pressure and elevated expression of AGT and AT1R in several adipose depots. That certain AT1R blockers exhibit partial PPARγ agonist activity suggests an unexpected, yet physiologically uncertain, link between PPARγ and the RAS.15 What remained unclear is whether this association between PPARγ and the RAS is clinically relevant?In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Caron-Debarle et al16 explore this question in 4 members of 2 unrelated families with familial partial lipodystrophy associated with early-onset severe hypertension. Blood pressure control in these patients required aggressive treatment with multiple antihypertensive agents (including AT1R blockers) concurrent with treatment for hyperlipidemia, and in 3 of the 4 subjects, diabetes mellitus. They identified 2 previously unreported mutations in PPARγ. R165T occurs in a highly conserved residue in the DNA-binding domain, whereas L339X truncates the protein to lack a portion of the ligand-binding domain. All 4 patients were heterozygous for one of the mutations. In vitro studies of cultured fibroblasts and peripheral blood mononuclear cells derived from the patients, as well as human vascular smooth muscle cells transfected with the PPARγ mutants revealed that the mutant and wild-type alleles were equivalently expressed, but the mutants lacked transactivation capability. Unlike other mutations in PPARγ that cause hypertension, they do not act dominant negatively and most likely cause haploinsufficiency.3 TZD treatment improved glycemic control and eliminated the need for high-dose insulin therapy in 2 subjects, suggesting that the potential to activate the wild-type PPARγ allele was preserved. Although untested in the current study, it is possible that the activity of the wild-type PPARγ may have been impaired in these patients. Inflammation has been reported to impair PPARγ activity by cyclin-dependent kinase-5-mediated phosphorylation, an effect prevented by TZDs.17 Indeed, hypertension and diabetes mellitus are commonly associated with inflammation and fibroblasts isolated from these patients, exhibited increased nuclear factor kappa B activity, markers of inflammation, and increased ROS. AT1R signaling is well known to cause inflammation and oxidative stress, and interestingly, expression of AT1R, renin, and AGT were all markedly increased in patient fibroblasts and peripheral blood mononuclear cells, cells we do not immediately associate with the RAS. The increase in AT1R expression occurred concomitantly with increased Ang-II–induced extracellular signal-regulated kinase phosphorylation, and AT1R silencing prevented the induction of ROS and inflammation, suggesting that some of the pathological consequences of the mutations may be mediated by AT1R activation.These data suggest a mechanism, whereby impaired PPARγ activity induces AT1R expression and signaling, which promotes oxidative stress and inflammation. That the silencing of AT1R in these cells also decreased expression of renin and AGT suggests their increase may be secondary to increased AT1R signaling. We could therefore hypothesize the existence (at least in the isolated cells from these patients) of a feed-forward mechanism, whereby elevated AT1R action augments further Ang-II production that may then amplify the pathological response (see Figure). It is interesting to note that the induction of renin expression by AT1R in fibroblasts and peripheral blood mononuclear cells is contrary to Ang-II–induced inhibition of renin expression in kidney. Unfortunately, information regarding the status of the systemic RAS in these patients before treatment was not available, whereas under therapy, 2 patients had normal plasma renin activity, plasma and urinary aldosterone, and potassium. Although the clinical relevance of the RAS in fibroblasts and peripheral blood mononuclear cells remains uncertain, AT1R signaling in vascular smooth muscle cells is of obvious importance in the regulation of vasomotor function. A feed-forward mechanism, as described above, could potentially induce endothelial dysfunction and smooth muscle contraction, and exacerbate the hypertension.Download figureDownload PowerPointFigure. The peroxisome proliferator-activated receptor γ (PPARγ):renin–angiotensin system (RAS) relationship. Schematic showing that PPARγ mutations cause an increase in expression of the AT1 receptor (AT1R), which induces hypertension perhaps through reactive oxygen species (ROS) and inflammation. The increase in renin and angiotensinogen (AGT) elevates production of angiotensin-II (Ang-II), which in cells from the affected patients, causes a feed-forward mechanism, which may further increase AT1R signaling. Thiazolidinedione (TZD) treatment activates the wild-type PPARγ allele and blunts the effects of the mutation. A similar effect is attained by blocking AT1R expression by small interfering RNA, and presumably with AT1R blockers.Regardless of the many strengths of this translational study, a number of important questions remain. First, did TZD treatment of the affected patients have an effect on arterial pressure; or in a more general sense, does PPARγ activation lower blood pressure in humans by antagonizing the RAS? We know that treatment of the patient fibroblasts with rosiglitazone, which presumably activated wild-type PPARγ, decreased expression of the RAS genes, and blunted the increase in ROS, nuclear factor kappa B, and interleukin-6 induced by the PPARγ mutations. Thus, at the cellular level, a normal phenotype could be rescued by activation of wild-type PPARγ by TZD. Even with the declining clinical use of TZDs, this may be important because new PPARγ activators, which do not act as full PPARγ agonists, are in development. At least one of these new compounds prevents impairment of PPARγ activity by posttranslational mechanisms induced by inflammation, and importantly, this compound may lack some of the detrimental side effects of TZDs.18 Its effect on the cardiovascular system has yet to be explored. Second, is the AT1R gene the primary PPARγ target gene or are there other PPARγ target genes in the relevant tissues, which become dysregulated in response to mutant PPARγ? We recently reported that PPARγ induces expression of a target gene in the aorta, which controls the activity of the Cullin-3 pathway, a regulator of RhoA/Rho kinase signaling and vasomotor function.19 We also recently identified a physiological connection between PPARγ and AT1R activity (but not AT1R expression) in mesenteric resistance vessels through Regulator of G-protein signaling 5, a novel PPARγ target gene that functions as a small GTPase-activating protein to regulate AT1R signaling.20 Third, are all the cardiovascular effects in these patients mediated by PPARγ and the RAS? This may be important to consider because there are other inherited lipodystrophies that are not caused by mutations in PPARγ, yet are associated with hypertension.21,22 A common feature of all these disorders is insulin resistance and a loss or redistribution of adipose tissue (eg, loss of subcutaneous adipose with accumulation of abdominal adipose).23 The mechanistic contributions of these features to hypertension in these patients remains unclear. Interestingly, as these patients often display evidence of inflammation (eg, increased plasma C-reactive peptide), a role for impaired PPARγ activity, and thus increased RAS activity, should be considered.In closing, there are other familial partial lipodystrophy associated with early-onset severe hypertension subjects that carry different mutations in PPARγ and exhibit a much broader array of neurological and hematological symptoms, in addition to severe metabolic syndrome.24 It is therefore likely that PPARγ has far-reaching effects that may extend beyond RAS. Studies of human patients and patient cells like Caron-Debarle et al16 combined with studies using animal models will likely uncover other mechanistic links between PPARγ, the RAS, and other important pathways that may lead to effective therapies for the spectrum of disorders that encompass the metabolic syndrome.Sources of FundingThis work was supported by National Institutes of Health grants HL048058, HL061446, HL062984, and HL084207 to C.D.S. The author also gratefully acknowledges the generous research support of the Roy J. Carver Trust.DisclosuresNone.FootnotesCorrespondence to Curt D. Sigmund, PhD, Roy J. Carver Chair of Hypertension Research, Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242. E-mail [email protected]