title: Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3.
abstract: Tubulointerstitial fibrosis (TIF) is one of the major problems in nephrology because satisfactory therapeutic strategies have not been established. Here, we demonstrate that maxacalcitol (22-oxacalcitriol (OCT)), an analog of active vitamin D, protects the kidney from TIF by suppressing the autoinduction of transforming growth factor-β1 (TGF-β1). OCT suppressed the tubular injury index, interstitial volume index, collagen I positive area, and mRNA levels of extracellular matrix genes in unilateral ureteral-obstructed kidneys in rats. Although the renoprotective mechanism of active vitamin D in previous studies has been mainly attributed to the suppression of renin, OCT did not affect renal levels of renin or angiotensin II. We found that TGF-β1 itself induces its expression in a phospho-Smad3 (pSmad3)-dependent manner, and that OCT ameliorated TIF by abrogating this 'autoinduction'. Under the stimulation of TGF-β1, pSmad3 bound to the proximal promoter region of the TGF-β1 gene. Both OCT and SIS3, a Smad3 inhibitor, abrogated the binding of pSmad3 to the promoter and consequently attenuated the autoinduction. TGF-β1 increased both the nuclear levels of protein phosphatase Mg(2+)/Mn(2+)-dependent 1A (PPM1A), a pSmad3 phosphatase, and the interaction levels between the vitamin D receptor (VDR) and PPM1A. In the absence of OCT, however, the interaction between pSmad3 and PPM1A was weak; therefore, it was insufficient to dephosphorylate pSmad3. The PPM1A/VDR complex was recruited to pSmad3 in the presence of both TGF-β1 and OCT. This recruitment promoted the dephosphorylation of pSmad3 and attenuated the pSmad3-dependent production of TGF-β1. Our findings provide a novel approach to inhibit the TGF-β pathway in fibrotic diseases.
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Inoue
authors.forename: Isao
authors.initials: I
authors.lastname: Matsui
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hamano
authors.forename: Naohiko
authors.initials: N
authors.lastname: Fujii
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shimomura
authors.forename: Chikako
authors.initials: C
authors.lastname: Nakano
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kusunoki
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Takabatake
authors.forename: Michinori
authors.initials: M
authors.lastname: Hirata
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Tsubakihara
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology; D000071636:Protein Phosphatase 2C; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000378:metabolism*; D012083:Renin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D016326:Extracellular Matrix Proteins; D020011:Protective Agents; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D012083:Renin; D002117:Calcitriol; C051883:maxacalcitol