Previously, we found decreased GH-stimulated janus-kinase 2-signal transducers and activators of transcription 5 (STAT5)
phosphorylation and nuclear translocation in uremia; however, it is unclear whether there are more distal defects. Therefore, we tested whether the binding of phosphorylated STAT5b to DNA is intact in uremia. Using uremic rats we found that in addition to impaired hepatic STAT5b phosphorylation, the binding of available phospho-STAT5b to DNA is decreased thus contributing to impaired IGF-1 gene expression. As sepsis-induced inflammation causes a loss of body protein and as Gram-negative infections are relatively common in uremia, we also characterized mechanisms in which acute inflammation might contribute to GH resistance in uremia. Endotoxin-induced this website inflammation click here markedly increased the resistance to GH-mediated STAT5b signaling, and further decreased STAT5b binding
to DNA and IGF-1 gene expression. These perturbations appear to be related to increased cytokine expression. Thus, our findings indicate that hepatic resistance to GH-induced IGF-1 expression in uremia arises due to defects in STAT5b phosphorylation and its impaired binding to DNA, processes further aggravated by inflammation. Kidney International (2010) 78, 89-95; doi: 10.1038/ki.2010.85; published online 7 April 2010″
“Nephron number varies widely between 0.3 and 1.3 million per kidney Thymidine kinase in humans. During fetal life, the rate of nephrogenesis is influenced by local retinoic acid (RA) level such that even moderate maternal vitamin A deficiency limits the final nephron number in rodents. Inactivation of genes in the RA pathway
causes renal agenesis in mice; however, the impact of retinoids on human kidney development is unknown. To resolve this, we tested for associations between variants of genes involved in RA metabolism (ALDH1A2, CYP26A1, and CYP26B1) and kidney size among normal newborns. Homozygosity for a common (1 in 5) variant, rs7169289(G), within an Sp1 transcription factor motif of the ALDH1A2 gene, showed a significant 22% increase in newborn kidney volume when adjusted for body surface area. Infants bearing this allele had higher umbilical cord blood RA levels compared to those with homozygous wild-type ALDH1A2 rs7169289(A) alleles. Furthermore, the effect of the rs7169289(G) variant was evident in subgroups with or without a previously reported hypomorphic RET 1476(A) proto-oncogene allele that is critical in determining final nephron number. As maternal vitamin A deficiency is widespread in developing countries and may compromise availability of retinol for fetal RA synthesis, our study suggests that the ALDH1A2 rs7169289(G) variant might be protective for such individuals. Kidney International (2010) 78, 96-102; doi: 10.1038/ki.2010.