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Lab Invest. 2012 Dec;92(12):1686-97. doi: 10.1038/labinvest.2012.107. Epub 2012 Aug 27.

Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3.

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1
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Japan.

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.

PMID:
22926646
DOI:
10.1038/labinvest.2012.107
[Indexed for MEDLINE]
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