Importantly, ATRA regulates APCs and T cells in a cell type- and context-dependent manner63. belief is that insights into interactive pathways in other PRKACA settings may be worth exploring in nephrology research. Retinoids are a family of vitamin A metabolites or analogs, including (i) natural provitamin A, vitamin A, and other retinoic acid precursors, which cannot bind retinoid nuclear receptors, but are characterized by their potential to be converted into retinoic acids; (ii) natural Docebenone retinoic acids, including all-TGF- signaling. It was reported that ATRA suppresses the TGF- superfamily member BMP4 by enhancing ubiquitin-mediated degradation of pSMAD1; future studies might address whether similar mechanisms are operative in TGF- signaling3. With similar action but via a secreted mediator, 9-cis-retinoic acid suppresses TGF–mediated induction of several pro-fibrotic molecules, e.g., fibronectin and plasminogen activator inhibitor-1 (PAI-1), in cultured human mesangial cells and this effect is mediated by the stimulation of hepatocyte growth factor4. In isolated heart tissue and in cultured NIH-3T3 fibroblasts, ATRA increases TGF- stimulated pSMAD2 and pSMAD3, but decreases nuclear accumulation of these transcription factors and decreases pSMAD-mediated transcriptional activity5. Third, retinoids may TGF- signaling, via transcriptional and post-translational mechanisms. ATRA increases TGF- transcript levels and TGF-1 protein production by PC12 cells, acting on the TGF-1 promoter6. In mesenchymal stem cells, ATRA induces SMAD RNA expression and protein nuclear localization7. In retinal pigment epithelial cells, ATRA increases expression of thrombospondin-1 and this in turn converts TGF-1 to Docebenone its active form8. ATRA induces production of TGF-2 by pancreatic cancer cells in vitro, as discussed further below9. Fourth, TGF- may affect tissue levels of retinoid ligands and expression of nuclear receptors. For example, Alb/TGF-1 transgenic mice have reduced tissue levels of retinoids10; TGF-1 induces expression of RARs and RXRs in osteoblasts 11and inhibits Cyp26b1, a metabolizing enzyme of ATRA, in T cells12. Embryonic and fetal development Retinoids/RAR and TGF- are involved in embryogenesis and organ development, with significant crosstalk between the two pathways13C17. Retinoids and TGF- also have crosstalk in embryonic stem cells. In embryonic stem cells, ATRA induces the expression of Foxa1, which acts as a pioneer transcription factor, binding and poising chromatin for intersection with the TGF–induced SMAD signaling, and cooperates with the latter in activation of -fetoprotein gene expression17. In C2C12 mouse myoblasts, both ATRA and 9 exposure of the developing mouse inner ear to a high dose of ATRA results in severe malformations of the inner ear that are associated with diminished levels of endogenous TGF-1, TGF- type II receptor and Smad2 in the inner ear, while suppression of RAR expression by an antisense oligonucleotide leads to a reduction in endogenous TGF-1 and a marked suppression of chondrogenesis, which can be partially rescued by exogenous TGF-1. Thus, TGF-1 may play important roles in the physiologic and pathologic effects of RA on inner ear development28. Retinoid/TGF- crosstalk may contribute to kidney development but a definitive role remains to be established. In the induction of avian pronephros (the first kidney to arise in development), the neural tube releases TGF- family member activin, and competence of the intermediate mesoderm cells to respond and differentiate appears to be driven by retinoic acid-dependent expression of Hoxb4, a critical transcription factor29. RXR/RAR-mediated canonical transcriptional activity is predominantly located in the ureteric bud lineage of the pre- and post-natal kidneys30 and mice with specific deletion of TGF- type II receptor from the ureteric bud lineage develop grossly normal kidneys do not support indispensable crosstalk between the two pathways in the ureteric bud31. Neoplasia Retinoids are approved for promyelocytic leukemia; acting as a differentiating agent, it has substantially improved patient outcomes. In HL-60 human promyelocytic leukemia cells, TGF-1 enhances ATRA-induced suppression of cell proliferation and inhibits ATRA-induced apoptosis32; while ATRA directs differentiation to granulocytes in a RAR-dependent manner, TGF- SMAD2/3-dependently directs differentiation to monocytes; simultaneous treatment of these cells with TGF-1 and RA, which leads to almost equal numbers of granulocytes and monocytes, significantly reduced the level of phospho-Smad2/3 and its nuclear accumulation, compared with that in cells treated with TGF-1 alone33. ATRA also reduces expression of microRNA-146A in an acute promyeloctyic cell line; this microRNA targets SMAD4, and thus the effect is to increase TGF- signaling34. ATRA Docebenone also promotes differentiation of Wilms tumor cells, normalizing the expression of multiple genes associated with the neoplastic phenotype35. Human concentrative nucleoside transporter-3 (hCNT3) is a sodium-coupled nucleoside transporter that exhibits high affinity and broad substrate selectivity, making it the most suitable candidate for mediating the uptake and cytotoxic action of most nucleoside-derived drugs. The drug of this class most commonly used in the treatment of chronic lymphocytic leukemia (CLL) is the pro-apoptotic nucleoside analog fludarabine (Flu), which enters CLL cells primarily through human equilibrative nucleoside transporters (hENTs). Although CLL cells lack hCNT3 activity, they do express this transporter protein, which is located.
