PPAR-γ activation inhibits angiotensin II synthesis, apoptosis, and proliferation of mesangial cells from spontaneously hypertensive rats

Background/ Aim: The angiotensin II level is elevated in subjects genetically prone to develop hypertension, triggering renal hypercellularity, cytokine production, and matrix deposition. Angiotensin- converting enzyme inhibition and/ or angiotensin II type 1 receptor blockade attenuate renal damage. Rosiglitazone, a peroxisome proliferator- activated receptor gamma agonist possessing antihypertensive and anti- inflammatory properties, was demonstrated to provide better renal protection than angiotensin- converting enzyme inhibitors. We studied the effects of in vivo peroxisome proliferator- activated receptor gamma activation by rosiglitazone on angiotensin II synthesis, proliferation, and apoptosis of mesangial cells of spontaneously hypertensive rats versus normotensive Sprague- Dawley rats. Methods: The animals consumed either a high- sodium diet ( 8% Na) or a normal- sodium diet ( 0.5% Na). Half of each group received rosiglitazone at 5 mg/ kg/ day. After 3 weeks, all rats were sacrificed and the mesangial cells isolated and cultured. Angiotensin II was assessed by radioimmunoassay, apoptosis by terminal deoxynucleotidyl transferase- mediated dUTP nickend labeling assay, and cell proliferation by [H-3] thymidine incorporation. Results: Only the spontaneously hypertensive rats which consumed the high- sodium diet developed hypertension ( 185 +/- 6 mm Hg vs. basal 128 +/- 5 mm Hg; p = 0.0007) which was attenuated by rosiglitazone ( to 126 8 4 mm Hg; p = 0.34). Angiotensin II synthesis, proliferation, and apoptosis were exaggerated in mesangial cell cultures from Sprague- Dawley rats and, more so, spontaneously hypertensive rats fed the high- sodium diet, but were inhibited in cultures from rosiglitazone- treated animals. Conclusions: Peroxisome proliferator- activated receptor gamma activation, in addition to lowering blood pressure, suppresses angiotensin II synthesis and downregulates angiotensin- II- mediated proliferation and apoptosis of mesangial cells. In the context of hypertension- induced renal damage, this would mean that the renoprotective role of rosiglitazone extends beyond glycemic and lipidemic control.