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Progression of chronic kidney disease associated with progressive fibrosis and impaired tubular epithelial regeneration is still an unmet biomedical challenge because, once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. Prompted by various studies across multiple organs demonstrating that preconditioning regimens to induce endogenous regenerative mechanisms protect various organs from later incurring acute injuries, we here aimed to gain insights into the molecular mechanisms underlying successful protection and to explore whether such pathways could be utilized to inhibit progression of chronic organ injury. We identified a protective mechanism controlled by the transcription factor ARNT that effectively inhibits progression of chronic kidney injury by transcriptional induction of ALK3, the principal mediator of antifibrotic and proregenerative bone morphogenetic protein-signaling (BMP-signaling) responses. We further report that ARNT expression itself is controlled by the FKBP12/YY1 transcriptional repressor complex and that disruption of such FKBP12/YY1 complexes by picomolar FK506 at subimmunosuppressive doses increases ARNT expression, subsequently leading to homodimeric ARNT-induced ALK3 transcription. Direct targeting of FKBP12/YY1 with in vivo morpholino approaches or small molecule inhibitors, including GPI-1046, was equally effective for inducing ARNT expression, with subsequent activation of ALK3-dependent canonical BMP-signaling responses and attenuated chronic organ failure in models of chronic kidney disease, and also cardiac and liver injuries. In summary, we report an organ-protective mechanism that can be pharmacologically modulated by immunophilin ligands FK506 and GPI-1046 or therapeutically targeted by in vivo morpholino approaches., Introduction Progression of chronic kidney disease (CKD) toward end-stage renal disease (ESRD) is an unmet biomedical challenge, just like chronic progressive failure of any other parenchymal organ, because effective therapies [...]

Differentiation of the embryonic stem cells (ESCs) is regulated by a variety of different signaling pathways. Genetic depletion of murine Pelota gene (Pelo) leads to early embryonic lethality. Here, we aimed at determining the embryonic stage and deciphering the dysregulated signaling pathways affected upon Pelo deletion. We found that development of PELO‐null embryos is perturbed between the embryonic days E4.5 and E5.5, at which first differentiation process of ESCs takes place. Molecular analysis revealed enhanced activity of phosphoinositide 3‐kinase–protein kinase B/ AKT (PI3K‐PKB/AKT) signaling, but nuclear accumulation of forkhead box O1 (FOXO1), and upregulation of the pluripotency‐related gene, Oct4, in mutant ESCs cultured under differentiation condition. Despite increased levels of nuclear β‐catenin in PELO‐null ESCs as a result of decreased activity of glycogen synthase kinase‐3β, the activity of the canonical wingless (Wnt)/β‐catenin/T‐cell factor (TCF) was significantly attenuated as judged by the promoter reporter assay, downregulated Wnt/β‐catenin target genes, and impaired cell proliferation. Interestingly, we demonstrated an increased binding of β‐catenin to FOXO1 in PELO‐mutant ESCs cultured under differentiation condition that could explain, on one side, the nuclear accumulation of FOXO1 protein and hence persistent pluripotency of PELO‐mutant ESCs, and on the other side, the dysregulated transcriptional activity of β‐catenin/TCF and therefore attenuated PELO‐null ESC self‐renewal. Taken together, our results strongly suggest that PELO deletion averts ESC differentiation through promoting FOXO1/β‐catenin binding with subsequent dysregulation of FOXO1 and canonical β‐catenin/TCF signaling pathways. [ABSTRACT FROM AUTHOR]