Interleukin-6 stimulates -MG uptake in renal proximal tubule cells: involvement of STAT3, PI3K/Akt, MAPKs, and NF- B

Lee YJ, Heo JS, Suh HN, Lee MY, Han HJ. Interleukin-6 stimulates -MG uptake in renal proximal tubule cells: involvement of STAT3, PI3K/Akt, MAPKs, and NFB. Am J Physiol Renal Physiol 293: F1036–F1046, 2007. First published June 20, 2007; doi:10.1152/ajprenal.00034.2007.—Recent studies have shown that interleukin 6 (IL-6) acts on the cellular proliferation-activating transduction signals during cellular regeneration. Therefore, this study examined the effect of IL-6 on the activation of Na /glucose cotransporters (SGLTs) and its related signaling pathways in primary cultured renal proximal tubule cells (PTCs). IL-6 increased the level of -methyl-D-[C]glucopyranoside ( -MG) uptake in timeand dosedependent manners. IL-6 also increased SGLT1 plus SGLT2 mRNA and protein expression level. The IL-6 receptors (IL-6R and gp130) were expressed in PTCs. In addition, genistein and herbimycin A completely blocked the IL-6-induced increases in -MG uptake and the protein expression level of SGLTs. On the other hand, IL-6 increased the level of 5-(and-6)-chloromethyl-2 ,7 -dichlorodihydrofluorescein diacetate-sensitive cellular reactive oxygen species (ROS), and IL-6-induced increases in -MG uptake and the protein expression level of SGLTs were blocked by ascorbic acid or taurine (antioxidants). IL-6 also increased the phosphorylation of signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3 kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) in a time-dependent manner. A pretreatment with STAT3 inhibitor LY 294002, an Akt inhibitor, or MAPK inhibitors significantly blocked the IL-6-induced increase in -MG uptake. In addition, IL-6 increased the level of nuclear factorB (NFB) phosphorylation. A pretreatment with SN50 or BAY 11-7082 also blocked the IL-6-induced increase in -MG uptake. In conclusion, IL-6 increases the SGLT activity through ROS, and its action in renal PTCs is associated with the STAT3, PI3K/Akt, MAPKs, and NFB signaling pathways.