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

CD Sigmund - Arteriosclerosis, thrombosis, and vascular biology, 2013 - Am Heart Assoc
Arteriosclerosis, thrombosis, and vascular biology, 2013Am Heart Assoc
Sigmund A Clinical Link Between PPARγ and the RAS 677 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 …
Sigmund A Clinical Link Between PPARγ and the RAS 677 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 feedforward mechanism, as described above, could potentially induce endothelial dysfunction and smooth muscle contraction, and exacerbate the hypertension. 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
Am Heart Assoc