Therapeutic Role of TGF-β–Neutralizing Antibody in Mouse Cyclosporin A Nephropathy

Abstract

Abstract. TGF-␤ is believed to play a central role in the development of Cyclosporin A (CsA)-induced nephropathy. This study investigated the effects of 1D11, a murine panspecific TGF-␤-neutralizing monoclonal antibody, in an ICR mouse model of chronic CsA nephropathy. Mice were administered a low-salt diet (0.01% sodium) for 1 wk followed by CsA treatment (30 mg/kg, subcutaneously, daily) for 4 wk. 1D11 was administered (2.5 mg/kg, intraperitoneally, 3 times/ wk) beginning immediately after the termination of CsA dosing and continued through 8 wk. CsA caused extensive renal histopathologic alterations, including tubular damage, interstitial infiltrates and fibrosis, deposition of collagen III, and apoptosis of tubular epithelial cells. 1D11 ameliorated the CsA-induced histopathologic alterations, with significant reduction in collagen III expression and deposition. Additionally, elevated levels of mRNA encoding TGF-␤1 and TGF-␤2 were significantly reduced. 1D11 also protected tubular epithelial cells from apoptosis by 48% (P Ͻ 0.05). In contrast, 13C4 (a control antibody) had no significant effect on any of the endpoints described above. Importantly, the effects of 1D11 on the CsA-induced morphologic alterations were followed by a reduction in serum creatinine level when compared with CsA mice treated with 13C4 (13C4, 0.45 Ϯ 0.09; 1D11, 0.30 Ϯ 0.08; P Ͻ 0.05) after 8 wk of treatment. Endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), nitrotyrosine, and tissue hypoxia were examined by immunostaining using specific antibodies. eNOS was significantly reduced in the endothelium of arterioles in the kidneys of mice treated with CsA, whereas iNOS was induced in the cortical tubules. Tissue hypoxia was found in both the arterioles and tubules, whereas nitrotyrosine was localized in the tubules. Administration of 1D11 improved tissue hypoxia and reduced nitrotyrosine formation. Moreover, the reciprocal changes in iNOS and eNOS expression were normalized by 1D11. This study demonstrates that 1D11 administration ameliorated morphologic alterations and preserved renal function in the context of existing chronic CsA nephropathy.

The effects of Cyclosporin A and Heteropterys tomentosaon the rat liver

“…CsA-associated fibrosis is largely reported in the kidney (Bakker et al 2003, Ling et al 2003, Li et al 2004. Hagar (2004) working with CsA (25mg/kg daily), administered daily to rabbits, observed mild connective tissue proliferation in the liver periportal region.…”

Effect of combination therapy with enalapril and the TGF-β antagonist 1D11 in unilateral ureteral obstruction

“…It has been used as a single agent in several models of renal disease including UUO, diabetes, glomerulonephritis, and cyclosporine nephropathy (2,18,20,36). Similarly, either ACE inhibitors or ANG II antagonists have been used both clinically and experimentally in both renal and cardiac disease models (13,16,17,25,30).…”

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

“…35 A number of studies have implicated TGF-␤ as a key mediator of cyclosporine-induced nephrotoxicity, but definitive evidence has only recently been reported. Our laboratory 15 and those of others 36,37 have examined the effects of administering TGF-␤-neutralizing antibodies to nontransplantation models of cyclosporine nephrotoxicity. These studies have shown that blocking TGF-␤ can normalize the expression of collagen types III and I and substantially reduce overall tissue fibrosis when examined histologically.…”