Additive antifibrotic effects of pioglitazone and candesartan on experimental renal fibrosis in mice.
OBJECTIVE
To examine the additive protective effects of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone (Pio) and the angiotensin II receptor blocker candesartan (Cand) in a murine model of renal fibrosis: mice with unilateral ureteral obstruction (UUO).


METHODS
Mice were randomly assigned into four groups that after UUO received i.p. injections of either Pio (10 mg/kg/day), Cand (1 mg/kg/day), Cand + Pio or vehicle for 10 days. Physiological parameters, the degree of renal fibrosis and molecules related to renal fibrosis were analysed, and sham-operated mice were used as controls.


RESULTS
Total collagen assay showed prominent renal fibrosis in the vehicle-treated mice, significantly attenuated renal fibrosis in the Cand-treated and the Pio-treated mice, and further attenuated renal fibrosis in the (Cand + Pio)-treated mice. Real-time reverse transcription polymerase chain reaction revealed that this attenuation pattern was also evident in the expression of the mRNA for transforming growth factor-beta, collagens I and III, and plasminogen activator inhibitor-1.


CONCLUSIONS
Pioglitazone and candesartan have additive protective effects on renal fibrosis due to UUO in mice, suggesting that their use in combination would be an effective treatment for chronic kidney disease.
Higashi
Keishi
K
Department of Nephrology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. dr21044@ndmc.ac.jp
Oda
Takashi
T
Kushiyama
Taketoshi
T
Hyodo
Toshitake
T
Yamada
Muneharu
M
Suzuki
Shigenobu
S
Sakurai
Yutaka
Y
Miura
Soichiro
S
Kumagai
Hiroo
H
D052242:Adiponectin / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds; D018932:Chemokine CCL2 / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D013777:Tetrazoles / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D052242:Adiponectin; C499919:Adipoq protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D015415:Biomarkers; D001713:Biphenyl Compounds; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D024061:Collagen Type III; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D013777:Tetrazoles; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; C081643:candesartan; D000077205:Pioglitazone