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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism
  • Animals
  • Base Sequence
  • Calcitriol / analogs & derivatives*
  • Calcitriol / pharmacology
  • Cell Line
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Fibrosis
  • Immunohistochemistry
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology*
  • Kidney Tubules / chemistry
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Male
  • Molecular Sequence Data
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Protective Agents / pharmacology
  • Protein Phosphatase 2C
  • RNA, Messenger
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Receptors, Calcitriol / metabolism*
  • Renin / metabolism
  • Signal Transduction / drug effects
  • Smad3 Protein / metabolism*
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Ureteral Obstruction / metabolism
  • Ureteral Obstruction / pathology


  • Extracellular Matrix Proteins
  • Protective Agents
  • RNA, Messenger
  • Receptors, Calcitriol
  • Smad3 Protein
  • Smad3 protein, rat
  • Transforming Growth Factor beta1
  • Angiotensin II
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C
  • Renin
  • Calcitriol
  • maxacalcitol