Ashwani K Khanna1, Galen M Pieper. 1. Division of Cardiology, University of Maryland, 22 S. Greene Street S-3B08, Baltimore, MD-21201, USA. akhanna@medicine.umaryland.edu
Abstract
BACKGROUND: 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. 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-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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. 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-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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Naif O Al-Harbi; Faisal Imam; Mohammed M Al-Harbi; Othman A Al-Shabanah; Moureq Rashed Alotaibi; Homood M As Sobeai; Muhammad Afzal; Imran Kazmi; Ammar Cherkess Al Rikabi Journal: Inflammopharmacology Date: 2019-01-01 Impact factor: 4.473
Authors: Naif O Al-Harbi; Faisal Imam; Mohammed M Al-Harbi; Muzaffar Iqbal; Ahmed Nadeem; Mohammed M Sayed-Ahmed; Ali D Alabidy; Ali F Almukhallafi Journal: Biomed Res Int Date: 2014-05-28 Impact factor: 3.411