title: TCV-116 inhibits interstitial fibrosis and HSP47 mRNA in rat obstructive nephropathy.
abstract: Unilateral ureteral obstruction (UUO) is a well established disease model leading to fibrosis of the obstructed kidney. In this model, involvement of enhanced renin-angiotensin system in the pathogenesis of interstitial fibrosis has been demonstrated. A 47-kDa heat-shock protein (HSP47) was originally identified as a collagen-binding stress protein, and is currently considered to be a collagen-specific molecular chaperone that plays a pivotal role during the biosynthesis and secretion of procollagen from endoplasmic reticulum. To test if HSP47 is involved in interstitial fibrosis in UUO, we examined the expression of HSP47 mRNA in rat UUO kidneys after 12 hours. 1, 4, 7 days of obstruction. HSP47 mRNA expression was significantly increased as early as 12 hours after obstruction and was sustained at the increased level until seven days. Type I collagen mRNA significantly increased after four days of UUO. Fibrotic changes of interstitium appeared in Masson's trichrome stained section after four days. To explore the possible involvement of angiotensin II (Ang II) in HSP47 induction, the effect of Ang II receptor antagonist (TCV-116) and angiotensin converting enzyme inhibitor (lisinopril) was tested. TCV-116 or lisinopril was given to the animals orally once a day at the dose of 10 mg/kg. TCV-116 or lisinopril significantly ameliorated the fibrotic change of interstitium seven days after obstruction. HSP47 and type I collagen mRNA levels in the TCV-116- or lisinopril-treated groups were reduced to about 60% of untreated UUO. A possible involvement of HSP47 in the pathogenesis of interstitial fibrosis in UUO is suggested; however, further investigation is required to identify the signals involved in the induction of HSP47 in UUO.
authors.affiliation: First Department of Medicine, Osaka University School of Medicine, Faculty of Health, Japan. toshiki@medone.med.osaka-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Moriyama
authors.forename: N
authors.initials: N
authors.lastname: Kawada
authors.forename: Y
authors.initials: Y
authors.lastname: Akagi
authors.forename: A
authors.initials: A
authors.lastname: Ando
authors.forename: M
authors.initials: M
authors.lastname: Horio
authors.forename: A
authors.initials: A
authors.lastname: Yamauchi
authors.forename: K
authors.initials: K
authors.lastname: Nagata
authors.forename: E
authors.initials: E
authors.lastname: Imai
authors.forename: M
authors.initials: M
authors.lastname: Hori
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D003094:Collagen / Q000096:biosynthesis; D005355:Fibrosis; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006651:Histocytochemistry; D008297:Male; D011355:Prodrugs / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles; D014517:Ureteral Obstruction / Q000150:complications* / Q000473:pathology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D011355:Prodrugs; D012333:RNA, Messenger; C494662:Serpinh1 protein, rat; D013777:Tetrazoles; D000804:Angiotensin II; D003094:Collagen; C077793:candesartan cilexetil