Prevention of chronic allograft nephropathy with vitamin D.
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.
Hullett
Debra A
DA
Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, USA. hullett@surgery.wisc.edu
Laeseke
Paul F
PF
Malin
Gretchen
G
Nessel
Regina
R
Sollinger
Hans W
HW
Becker
Bryan N
BN
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*
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