Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3 - PubMed (original) (raw)
. 2012 Dec;92(12):1686-97.
doi: 10.1038/labinvest.2012.107. Epub 2012 Aug 27.
Isao Matsui, Takayuki Hamano, Naohiko Fujii, Akihiro Shimomura, Chikako Nakano, Yasuo Kusunoki, Yoshitsugu Takabatake, Michinori Hirata, Akira Nishiyama, Yoshiharu Tsubakihara, Yoshitaka Isaka, Hiromi Rakugi
Affiliations
- PMID: 22926646
- DOI: 10.1038/labinvest.2012.107
Free article
Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3
Kazunori Inoue et al. Lab Invest. 2012 Dec.
Free article
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.
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