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

Abstract

A 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 829 PPARγ 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.7,8 Data suggesting a role for PPARγ in regulating blood pressure led many to search for downstream …