Chronic proteinuric renal injury is a major cause of ESRD. Adriamycin nephropathy is a murine model of chronic proteinuric renal disease whereby chemical injury is followed by immune and structural changes that mimic human disease. Foxp3 is a gene that induces a regulatory T cell (Treg) phenotype. It was hypothesized that Foxp3-transduced Treg could protect against renal injury in Adriamycin nephropathy. CD4؉ T cells were transduced with either a Foxp3-containing retrovirus or a control retrovirus. Foxp3-transduced T cells had a regulatory phenotype by functional and phenotypic assays. Adoptive transfer of Foxp3-transduced T cells protected against renal injury. Urinary protein excretion and serum creatinine were reduced (P < 0.05), and there was significantly less glomerulosclerosis, tubular damage, and interstitial infiltrates (P < 0.01). It is concluded that Foxp3-transduced Treg cells may have a therapeutic role in protecting against immune injury and disease progression in chronic proteinuric renal disease.

TGF- is a key profibrotic factor, but targeting TGF- to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF- signaling by preventing downstream profibrotic interaction of -catenin with T cell factor (TCF), thereby enhancing the interaction of-catenin with Foxo, a transcription factor that controls differentiation of TGF- induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF- In iTregs derived from EL4 T cells treated with recombinant human TGF-1 (rhTGF-1) , inhibition of-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of -catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3 Ly5.1/5.2 mice revealed that coadministration of rhTGF-1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-1 treatment alone. Coadministration of rhTGF-1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF-1. Together, our results show that diversion of -catenin from TCF- to Foxo-mediated transcription inhibits the-catenin/TCF-mediated profibrotic effects of TGF- while enhancing the -catenin/Foxo-mediated anti-inflammatory effects. Targeting-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.

Regulatory T cells (Tregs) help protect against autoimmune renal injury. The use of agonist antibodies and antibody/cytokine combinations to expand Tregs in vivo may have therapeutic potential for renal disease. Here, we investigated the effects of administering IL-2/IL-2Ab complexes in mice with adriamycin nephropathy, a model of proteinuric kidney disease that resembles human focal segmental glomerulosclerosis. Injecting IL-2/IL-2Ab complexes before or, to a lesser extent, after induction of disease promoted expansion of Tregs. Furthermore, administration of this complex was renoprotective, evidenced by improved renal function, maintenance of body weight, less histologic injury, and reduced inflammation. IL-2/IL-2Ab reduced serum IL-6 and renal expression of IL-6 and IL-17 but enhanced expression of IL-10 and Foxp3 in the spleen. In vitro, the addition of IL-2/IL-2Ab complexes induced rapid STAT-5 phosphorylation in CD4 T cells. In summary, these data suggest that inducing the expansion of Tregs by administering IL-2/IL-2Ab complexes is a possible strategy to treat renal disease.

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CD39 is an ecto-enzyme that degrades extracellular nucleotides, such as ATP, and is highly expressed on by the vasculature and circulating cells including IntroductionATP exists in high concentrations intracellularly and is the energy currency for cellular metabolism. Under pathophysiological con-