Interleukin-6 stimulates alpha-MG uptake in renal proximal tubule cells: involvement of STAT3, PI3K/Akt, MAPKs, and NF-kappaB.
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 alpha-methyl-d-[(14)C]glucopyranoside (alpha-MG) uptake in time- and dose-dependent manners. IL-6 also increased SGLT1 plus SGLT2 mRNA and protein expression level. The IL-6 receptors (IL-6Ralpha and gp 130) were expressed in PTCs. In addition, genistein and herbimycin A completely blocked the IL-6-induced increases in alpha-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 alpha-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 alpha-MG uptake. In addition, IL-6 increased the level of nuclear factor-kappaB (NF-kappaB) phosphorylation. A pretreatment with SN50 or BAY 11-7082 also blocked the IL-6-induced increase in alpha-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 NF-kappaB signaling pathways.
Lee
Yu Jin
YJ
Department of Veterinary Physiology, Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
Heo
Jung Sun
JS
Suh
Han Na
HN
Lee
Min Young
MY
Han
Ho Jae
HJ
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008757:Methylglucosides / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051247:Sodium-Glucose Transport Proteins / Q000378:metabolism
D015850:Interleukin-6; D008757:Methylglucosides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D051247:Sodium-Glucose Transport Proteins; C027020:methylglucoside; D019869:Phosphatidylinositol 3-Kinases; D020929:Mitogen-Activated Protein Kinase Kinases