NDT Advance Access originally published online on November 3, 2006
Nephrology Dialysis Transplantation 2007 22(2):376-385; doi:10.1093/ndt/gfl608
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NADPH oxidase subunits (NOX-1, p22phox, Rac-1) and tacrolimus-induced nephrotoxicity in a rat renal transplant model
1Division of Cardiology, University of Maryland, Baltimore, MD, 2Transplantation Unit, OncoDetect Inc., Brookfield, WI and 3Surgery (Transplant Surgery) and 4Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
Correspondence and offprint requests to: Ashwani Khanna, PhD, Division of Cardiology, University of Maryland, 22 S Greene Street S 3B08, Baltimore, MD-21201, USA. Email: akhanna{at}medicine.umaryland.edu
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Abstract |
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Background. TGF-ß and oxidative stress are known mediators of renal injury. However, the precise mechanisms by which TGF-ß and oxidative stress may be involved in the development of nephrotoxicity are not known. We examined whether anti-TGF-ß antibody limits nephrotoxicity produced by tacrolimus (TAC) and whether this altered genes that regulate oxidative stress.
Methods. Renal transplants were performed in Wistar-Furth and Lewis rat strains. Groups included: isograft controls; untreated allografts; allografts treated with 0.25 mg/kg TAC till 90 days with or without 1.0 mg/kg anti-TGF-ß antibody or control antibody. Serum creatinine and BUN levels and renal histology were determined. Real time PCR and western analysis were used to quantify mRNA and protein expression.
Results. BUN and creatinine were elevated in TAC-treated rats. TAC increased expression of TGF-ß (37-fold) and NADPH oxidase subunits, NOX-1 (18-fold), p22phox (31-fold) and Rac-1 mRNA (20-fold), respectively. Contrariwise, expression of antioxidant genes, superoxide dismutase (SOD) and thioredoxin (TRX) was decreased. Anti-TGF-ß antibody but not control antibody reversed the TAC-induced changes in gene expression, renal histology and function.
Conclusions. Our findings suggest a potential for anti-TGF-ß antibody as a novel adjunct therapeutic tool to prevent TAC-induced nephrotoxicity in transplant recipients. The mechanism of protection involves suppression of TGF-ß and the expression of genes that regulate oxidative stress. Moreover, the specific up-regulation of NOX-1, a non-phagocytic NADPH oxidase subunit and its reversal by anti-TGF-ß antibody strongly implicates for the first time the up-regulation of renal parenchymal cell NADPH oxidase in the aetiology of immunosuppression-induced nephrotoxicity.
Keywords: anti-TGF-ß antibody; NADPH oxidase; nephrotoxicity; rat renal transplant model; tacrolimus; TGF-ß
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