title: PPAR-gamma activation inhibits angiotensin II synthesis, apoptosis, and proliferation of mesangial cells from spontaneously hypertensive rats.
abstract: OBJECTIVE
  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 nick-end labeling assay, and cell proliferation by [(3)H]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 +/- 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.
authors.affiliation: Nephrology Division, Department of Nephrology, Assaf Harofeh Medical Center, Zerifin, Israel. efratishai@013.net
authors.forename: Shai
authors.initials: S
authors.lastname: Efrati
authors.forename: Sylvia
authors.initials: S
authors.lastname: Berman
authors.forename: Eduard
authors.initials: E
authors.lastname: Ilgiyeav
authors.forename: Zhan
authors.initials: Z
authors.lastname: Averbukh
authors.forename: Joshua
authors.initials: J
authors.lastname: Weissgarten
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000804:Angiotensin II