NFAT5 Is Activated by Hypoxia: Role in Ischemia and Reperfusion in the Rat KidneyReportar como inadecuado

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The current hypothesis postulates that NFAT5 activation in the kidney’s inner medulla is due to hypertonicity, resulting incell protection. Additionally, the renal medulla is hypoxic 10–18 mmHg; however there is no information about the effectof hypoxia on NFAT5. Using in vivo and in vitro models, we evaluated the effect of reducing the partial pressure of oxygenPO2 on NFAT5 activity. We found that 1 Anoxia increased NFAT5 expression and nuclear translocation in primary culturesof IMCD cells from rat kidney. 2 Anoxia increased transcriptional activity and nuclear translocation of NFAT5 in HEK293 cells.3 The dose-response curve demonstrated that HIF-1a peaked at 2.5% and NFAT5 at 1% of O2. 4 At 2.5% of O2, the timecoursecurve of hypoxia demonstrated earlier induction of HIF-1a gene expression than NFAT5. 5 siRNA knockdown ofNFAT5 increased the hypoxia-induced cell death. 6 siRNA knockdown of HIF-1a did not affect the NFAT5 induction byhypoxia. Additionally, HIF-1a was still induced by hypoxia even when NFAT5 was knocked down. 7 NFAT5 and HIF-1aexpression were increased in kidney cortex and medulla from rats subjected to an experimental model of ischemia andreperfusion I-R. 7 Experimental I-R increased the NFAT5-target gene aldose reductase AR. 8 NFAT5 activators ATM andPI3K were induced in vitro HEK293 cells and in vivo I-R kidneys with the same timing of NFAT5. 8 Wortmannin, whichinhibits ATM and PI3K, reduces hypoxia-induced NFAT5 transcriptional activation in HEK293 cells. These results demonstratefor the first time that NFAT5 is induced by hypoxia and could be a protective factor against ischemic damage.

Autor: Villanueva, Sandra; - Suazo, Cristian; - Santapau, Daniela; - Pérez, Francisco; - Quiroz, Mariana; - Carreño, Juan E.; - Illane



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