NADPH oxidase subunits (NOX-1, p22(phox), Rac-1) and tacrolimus-induced nephrotoxicity in a rat renal transplant model

Department of Medicine, University of Maryland, Baltimore, Baltimore, Maryland, United States
Nephrology Dialysis Transplantation (Impact Factor: 3.58). 03/2007; 22(2):376-85. DOI: 10.1093/ndt/gfl608
Source: PubMed


TGF-beta and oxidative stress are known mediators of renal injury. However, the precise mechanisms by which TGF-beta and oxidative stress may be involved in the development of nephrotoxicity are not known. We examined whether anti-TGF-beta antibody limits nephrotoxicity produced by tacrolimus (TAC) and whether this altered genes that regulate oxidative stress.
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-beta 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.
BUN and creatinine were elevated in TAC-treated rats. TAC increased expression of TGF-beta (37-fold) and NADPH oxidase subunits, NOX-1 (18-fold), p22(phox) (31-fold) and Rac-1 mRNA (20-fold), respectively. Contrariwise, expression of antioxidant genes, superoxide dismutase (SOD) and thioredoxin (TRX) was decreased. Anti-TGF-beta antibody but not control antibody reversed the TAC-induced changes in gene expression, renal histology and function.
Our findings suggest a potential for anti-TGF-beta antibody as a novel adjunct therapeutic tool to prevent TAC-induced nephrotoxicity in transplant recipients. The mechanism of protection involves suppression of TGF-beta 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-beta antibody strongly implicates for the first time the up-regulation of renal parenchymal cell NADPH oxidase in the aetiology of immunosuppression-induced nephrotoxicity.

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    • "Several factors may contribute to the underlying mechanisms of nephrotoxicity, which include increased production of vasoconstriction factors, such as endothelin or thromboxane, and a decrease in vasodilation factors like prostacyclin, prostaglandin E2, and nitric oxide. TAC also has the ability to produce reactive oxygen species (ROS) via activation of NADPH oxidase pathway and cause disturbance in antioxidant defense which may be responsible for nephrotoxicity [7]. It has been reported that treatment with TAC leads to impairment in renin-angiotensin system (RAS) which may mediate nephrotoxicity [8] [9] [10]. "
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    ABSTRACT: Tacrolimus, a calcineurin inhibitor, is clinically used as an immunosuppressive agent in organ transplantation, but its use is limited due to its marked nephrotoxicity. The present study investigated the effect of olmesartan (angiotensin receptor blocker) on tacrolimus-induced nephrotoxicity in rats. A total of 24 rats were divided into four groups, which included control, tacrolimus, tacrolimus + olmesartan, and olmesartan groups. Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. Tacrolimus significantly increased BUN and creatinine level. Treatment with olmesartan reversed tacrolimus-induced changes in the biochemical markers (BUN and creatinine) of nephrotoxicity. Tacrolimus significantly decreased GSH level and catalase activity while increasing MDA level. Olmesartan also attenuated the effects of tacrolimus on MDA, GSH, and catalase. In tacrolimus group histological examination showed marked changes in renal tubule, mitochondria, and podocyte processes. Histopathological and ultrastructural studies showed that treatment with olmesartan prevented tacrolimus-induced renal damage. These results suggest that olmesartan has protective effects on tacrolimus-induced nephrotoxicity, implying that RAS might be playing role in tacrolimus-induced nephrotoxicity.
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    • "For instance, different members of the NADPH oxidase family have been recently related to TGF-β-induced signaling in different models. Effects in differentiation of cardiac fibroblasts [46], proliferation of pulmonary artery smooth cells [47] and nephrotoxicity [48] are controlled by a TGF-β-NADPH oxidase-dependent pathway. "
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