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Deprecated: Implicit conversion from float 302.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Cell+Physiol 2017 ; 232 (10): 2841-2850 Nephropedia Template TP
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Up-Regulation of Transient Receptor Potential Melastatin 6 Channel Expression by Tumor Necrosis Factor-alpha in the Presence of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor #MMPMID27925186
Furukawa C; Fujii N; Manabe A; Matsunaga T; Endo S; Hasegawa H; Ito Y; Yamaguchi M; Yamazaki Y; Ikari A
J Cell Physiol 2017[Oct]; 232 (10): 2841-2850 PMID27925186show ga
Anti-epidermal growth factor receptor (EGFR) drugs such as erlotinib and gefitinib cause a side effect of hypomagnesemia, but chemotherapy to treat this has not yet been developed. The transient receptor potential melastatin 6 (TRPM6) channel is involved in the reabsorption of Mg(2+) in the renal tubule. We reported previously that the expression of TRPM6 is up-regulated by epidermal growth factor (EGF) in renal tubular epithelial NRK-52E and HEK293 cells. EGF-induced elevation of TRPM6 expression was inhibited by erlotinib, gefitinib, and lapatinib. We found that tumor necrosis factor-alpha (TNF-alpha) increases TRPM6 expression in the presence of erlotinib. Therefore, we investigated what molecules are involved in the up-regulation of TRPM6 expression by TNF-alpha. EGF increased the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (p-ERK1/2), which were inhibited by erlotinib. TNF-alpha did not change p-ERK1/2 levels, but increased the phosphorylation and nuclear localization of nuclear factor-kappaB (NF-kappaB), which were blocked by the NF-kappaB inhibitors BAY 11-7082 and pyrrolidinedithiocarbamate ammonium. Similarly, luciferase reporter activity of human TRPM6 was increased by TNF-alpha, which was blocked by NF-kappaB inhibitors, and was inhibited by a mutation in the kappaB-binding site in the proximal region of the TRPM6 promoter. A chromatin immunoprecipitation assay revealed that NF-kappaB binds to the kappaB-binding site, which was blocked by NF-kappaB inhibitors. In the presence of erlotinib, TNF-alpha increased Mg(2+) influx, which was blocked by NF-kappaB inhibitors. These results suggest that TNF-alpha reverses the reduction in Mg(2+) reabsorption caused by anti-EGFR drugs. J. Cell. Physiol. 232: 2841-2850, 2017. (c) 2016 Wiley Periodicals, Inc.