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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/F1292    most recent 00232.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Omasu, F. Articles by Miura, S. Search for Related Content PubMed PubMed Citation Articles by Omasu, F. Articles by Miura, S.

Effects of pioglitazone and candesartan on renal fibrosis and the intrarenal plasmin cascade in spontaneously hypercholesterolemic rats

Departments of ¹Preventive Medicine and Public Health and ²Internal Medicine, National Defense Medical College, and ³Department of Internal Medicine, Hirose Hospital, Saitama, Japan

Submitted 17 May 2007 ; accepted in final form 26 July 2007

The profibrotic effect of plasminogen activator inhibitor-1 (PAI-1) in renal fibrosis is widely recognized, but its mechanism remains controversial especially in chronic progressive kidney disease. In the present study, pioglitazone (Pio) and candesartan (CD), which are reported to inhibit PAI-1, were administered to spontaneously hypercholesterolemic (SHC) rats, a model of chronic progressive kidney disease. Therapeutic effects and effects on the intrarenal plasmin cascade were examined. Eight-wk-old SHC rats were used as controls. Oral administration of vehicle alone, Pio, or CD was performed starting at 8 wk of age and was continued for 24 wk. The degree of renal fibrosis was evaluated by sirius red staining of kidney sections and by total collagen assay of renal homogenates. The renal PAI-1 protein level was assessed by Western blotting, and plasmin activity was analyzed by chromogenic assay and casein gel zymography. Urinary protein and blood urea nitrogen were significantly increased in the vehicle-treated group, but the increase was attenuated in the Pio- and CD-treated groups. This correlated well with the degree of fibrosis as assessed by sirius red staining and total collagen assay. The PAI-1 protein level was also increased significantly in the vehicle-treated group, and the increase was attenuated in the Pio- and CD-treated groups. Despite the presumed plasmin-inhibitory function of PAI-1, plasmin activity changed in parallel with PAI-1. These results suggest that Pio and CD inhibit PAI-1 and exert renoprotective effects against chronic progressive renal disease, but its action is independent of the regulatory function on plasmin activity.

angiotensin II type 1 receptor blocker; peroxisome proliferator-activated receptor- agonist; plasminogen activator inhibitor-1