Renoprotective properties of pirfenidone in subtotally nephrectomized rats.
Renal fibrosis is the final common pathway of chronic kidney disease, and its progression predicts the degree of renal dysfunction. We investigated the renoprotective properties of pirfenidone in a remnant kidney model of chronic renal failure to determine its pharmacological potency compared to enalapril. Five-sixths nephrectomized rats were fed diet containing pirfenidone (approximately 700mg/kg/day) for 8weeks. Pirfenidone steadily inhibited the progression of proteinuria, but not to a significant degree. Pirfenidone prevented the elevation of plasma creatinine and blood urea nitrogen. At the end of the experiment, pirfenidone had reduced systolic blood pressure by means of its renoprotective effect. In a histological study, pirfenidone improved interstitial fibrosis in the renal cortex. These effects were supported by the suppression of the expression of TGF-beta and fibronectin in the mRNA of the kidney. In contrast, pirfenidone had little effect on the expression of alpha-smooth muscle actin, which is one of the proteins responsible for epithelial-mesenchymal transition. This property was confirmed by the TGF-beta-induced transdifferentiation observed in cultured normal rat kidney tubular epithelial NRK52E cells. These results suggest that pirfenidone improves the progression of chronic renal failure via its antifibrotic action, although pirfenidone has less effective TGF-beta-induced epithelial to mesenchymal transdifferentiation.
Takakuta
Koji
K
Pharmacology Research Lab., Drug Discovery Research, Astellas Pharma Inc. 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. koji.takakura@jp.astellas.com
Fujimori
Akira
A
Chikanishi
Toshihiro
T
Tanokura
Akira
A
Iwatsuki
Yoshiyuki
Y
Yamamoto
Masanori
M
Nakajima
Hidenori
H
Okada
Masamichi
M
Itoh
Hiroyuki
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002908:Chronic Disease; D018450:Disease Progression; D004656:Enalapril / Q000494:pharmacology; D004847:Epithelial Cells / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000473:pathology; D009392:Nephrectomy; D011507:Proteinuria / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D011728:Pyridones; D016212:Transforming Growth Factor beta; D004656:Enalapril; C093844:pirfenidone