title: Prevention of chronic allograft nephropathy with vitamin D.
abstract: 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.
authors.affiliation: Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, USA. hullett@surgery.wisc.edu
authors.forename: Debra A
authors.initials: DA
authors.lastname: Hullett
authors.forename: Paul F
authors.initials: PF
authors.lastname: Laeseke
authors.forename: Gretchen
authors.initials: G
authors.lastname: Malin
authors.forename: Regina
authors.initials: R
authors.lastname: Nessel
authors.forename: Hans W
authors.initials: HW
authors.lastname: Sollinger
authors.forename: Bryan N
authors.initials: BN
authors.lastname: Becker
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D006084:Graft Rejection; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000379:methods*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014184:Transplantation, Homologous / Q000009:adverse effects; D014807:Vitamin D / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D051906:Smad7 Protein; C497808:Smad7 protein, rat; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014807:Vitamin D; D016572:Cyclosporine; D020782:Matrix Metalloproteinases