PMID- 16162105
OWN - NLM
STAT- MEDLINE
DCOM- 20051123
LR  - 20141113
IS  - 0934-0874 (Print)
IS  - 0934-0874 (Linking)
VI  - 18
IP  - 10
DP  - 2005 Oct
TI  - Prevention of chronic allograft nephropathy with vitamin D.
PG  - 1175-86
AB  - Chronic allograft nephropathy (CAN) is the leading cause of late allograft loss 
      in kidney transplantation. Interstitial fibrosis and glomerulosclerosis are 
      characteristic of CAN. Transforming growth factor beta-1 (TGFbeta-1) is 
      associated with both of these histologic findings in the transplant setting. 
      Recent studies have suggested that vitamin D signaling pathways may interact with 
      and regulate TGFbeta-1 mediated events. We examined the efficacy of 
      1,25-dihydroxyvitamin D(3), the active metabolite of vitamin D 
      [1,25-(OH)(2)D(3)], the active metabolite of vitamin D, as monotherapy to prolong 
      allograft survival and preserve renal function in a rat model of CAN, the Fisher 
      344 to Lewis model. Recipients went without treatment or were treated with 
      cyclosporine A (CSA; 10 days) or 1,25(OH)(2)D(3) (1000, 500 or 250 ng/kg/day). 
      Grafts were harvested at the time of rejection or at 24 weeks post-transplant. A 
      portion of the graft was processed for histology and immunohistochemistry and a 
      second portion was analyzed for protein expression by western blotting. Not only 
      did 1,25-(OH)(2)D(3) treatment significantly prolong graft survival, but it also 
      prevented histological changes associated with CAN. 1,25-(OH)(2)D(3) treatment 
      significantly decreased Smad 2 expression. This TGFbeta signaling molecule is 
      likely involved in fibrosis. Moreover, 1,25-(OH)(2)D(3) treatment increased Smad 
      7 expression, an important feedback molecule in the TGFbeta-1 signaling pathway. 
      This suggests that 1,25-(OH)(2)D(3) interacts with TGFbeta-1 in limiting 
      histological injury in this model of CAN. Furthermore, 1,25-(OH)(2)D(3), 
      treatment increased expression of matrix metalloproteinase 2 (MMP-2), thus 
      directly affecting levels of another important matrix molecule. Taken together 
      our data suggests that 1,25-(OH)(2)D(3) mitigates CAN in this model by altering 
      TGFbeta-1 and matrix-regulating molecules.
FAU - Hullett, Debra A
AU  - Hullett DA
AD  - Division of Transplantation, Department of Surgery, University of 
      Wisconsin-Madison, 600 Highland Avenue, Madison, WI, USA. 
      hullett@surgery.wisc.edu
FAU - Laeseke, Paul F
AU  - Laeseke PF
FAU - Malin, Gretchen
AU  - Malin G
FAU - Nessel, Regina
AU  - Nessel R
FAU - Sollinger, Hans W
AU  - Sollinger HW
FAU - Becker, Bryan N
AU  - Becker BN
LA  - eng
GR  - 1K24 DK 616962-03/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Switzerland
TA  - Transpl Int
JT  - Transplant international : official journal of the European Society for Organ 
      Transplantation
JID - 8908516
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Smad7 Protein)
RN  - 0 (Smad7 protein, rat)
RN  - 0 (Tgfb1 protein, rat)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 1406-16-2 (Vitamin D)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Chronic Disease
MH  - Cyclosporine/pharmacology
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Extracellular Matrix/metabolism
MH  - Fibrosis/metabolism
MH  - Graft Rejection
MH  - Graft Survival/drug effects/*immunology
MH  - Immunohistochemistry
MH  - Immunosuppressive Agents/pharmacology
MH  - Kidney Diseases/*etiology/*pathology
MH  - Kidney Transplantation/*adverse effects/*methods
MH  - Matrix Metalloproteinases/metabolism
MH  - Rats
MH  - Rats, Inbred F344
MH  - Rats, Inbred Lew
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - Smad7 Protein/metabolism
MH  - Time Factors
MH  - Transforming Growth Factor beta/metabolism
MH  - Transforming Growth Factor beta1
MH  - Transplantation, Homologous/adverse effects
MH  - Vitamin D/*chemistry/*therapeutic use
EDAT- 2005/09/16 09:00
MHDA- 2005/12/13 09:00
CRDT- 2005/09/16 09:00
PHST- 2005/09/16 09:00 [pubmed]
PHST- 2005/12/13 09:00 [medline]
PHST- 2005/09/16 09:00 [entrez]
AID - TRI187 [pii]
AID - 10.1111/j.1432-2277.2005.00187.x [doi]
PST - ppublish
SO  - Transpl Int. 2005 Oct;18(10):1175-86. doi: 10.1111/j.1432-2277.2005.00187.x.