Experimental cell research
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FGF23 is a bone-derived hormone that regulates systemic phosphate homeostasis, vitamin D metabolism and α-Klotho expression through a novel bone-kidney axis. FGF23 inhibits renal tubular reabsorption of phosphate through mechanisms independent of PTH as well as reduces circulating 1, 25(OH)(2)D through its dual effects to suppress Cyp27b1 production and to stimulate Cyp24 catabolism of 1,25(OH)(2)D. 1,25(OH)(2)D and other factors regulating bone remodeling/mineralization are the major physiological regulators of FGF23 expression. FGF23 also suppresses the gene transcription of α-klotho by the kidney, which exists as a membrane and soluble protein. ⋯ In addition, the prevalent thought that CKD is a functional "vitamin D deficient state" requiring therapy with 1,25(OH)(2)D analogs is challenged by effects of FGF23 to potentially lower both 25(OH)D and 1,25(OH)D by induction of Cyp24-mediated degradation. Finally, increments in FGF23 are associated with increased cardiovascular mortality in CKD. Whether these effects represent direct effects of FGF23 or represent a marker of other abnormalities in CKD remains to be determined.
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Erythropoietin (EPO) is an essential glycoprotein that facilitates red blood cell maturation from erythroid progenitors and mediates erythropoiesis. The use of recombinant human EPO (rhEPO) dramatically changed management of anemic patients with chronic kidney disease and improved their quality of life. EPO is mainly produced in the fetal liver and the postnatal kidney, although the molecular determinants for tissue-specific expression are elusive. ⋯ The precise signal transduction pathways of pleiotropic EPO remain unclear, but carbamylated EPO, which fails to bind to the canonical EPOR homodimers or transduce the JAK2-STAT5 signaling, conferred organ protection through multimeric receptors composed of EPO-R and the common β subunit (βCR). The clinical benefit of normalization of anemia in pre-dialysis CKD by EPO therapy is controversial and recent large-scale, randomized-controlled trials do not favor normalization of anemia by EPO in improving cardiovascular as well as renal outcomes. The optimal EPO therapy should be determined based on the clinical context of individual patients.