Mycophenolate mofetil modifies kidney tubular injury and Foxp3+ regulatory T cell trafficking during recovery from experimental ischemia-reperfusion

Abstract

Lymphocytes participate in the early pathogenesis of ischemia-reperfusion injury (IRI) in kidney; however, their role during repair is largely unknown. Recent data have shown that Foxp3+ regulatory T cells (Tregs) traffic into kidney during healing from IRI and directly participate in repair. Since lymphocyte-targeting therapy is currently administered to prevent rejection during recovery from IRI in renal transplants, we hypothesized that mycophenolate mofetil (MMF) would alter Treg trafficking and kidney repair. C57BL/6J and T cell deficient mice underwent unilateral clamping of renal pedicle for 45min, followed by reperfusion, and were sacrificed at day 10. Mice were treated with saline (C) or MMF (100mg/kg) i.p. daily starting at day 2 until sacrifice (n=5-12/group). MMF worsened kidney tubular damage compared to C at 10days (cortex and outer medulla: p<0.05) in wild-type mice; tubular apoptotic index was increased in cortex in MMF group as well (p=0.01). MMF reduced the total number of kidney-infiltrating mononuclear cells (p<0.001 versus C) and the percentages of TCRβ+CD4+ and TCRβ+CD8+ T cells (p<0.01), but not natural killer (NK), NKT or B lymphocytes. MMF specifically reduced kidney Foxp3+ Tregs (0.82±0.11% versus 1.75±0.17%, p<0.05). Tubular proliferative index and tissue levels of basic FGF were increased in MMF group (p<0.05), IL-10 and IL-6 were decreased (p<0.05). To evaluate if MMF effect occurred through non-lymphocytic cells, T cell deficient mice were treated with MMF. Tubular injury in T cell deficient mice was not affected by MMF treatment, though MMF-treated animals had increased VEGF and decreased PDGF-BB protein tissue levels compared to controls (p<0.05). Thus, MMF modifies the structural, epithelial proliferative and inflammatory response during healing, likely through effects on T cells and possibly Tregs. Kidney repair after IRI can be altered by agents that target lymphocytes. © 2010 Elsevier B.V.