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 ¹⁴C--methyl-D-glucopyranoside (-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-6 subunit (IL-6R) and IL-6 subunit (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 (CM-H₂DCF-DA)-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. 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, Akt inhibitor, PD 98059, SB 203580, or SP 600125 significantly blocked the IL-6-induced increase in -MG uptake. In addition, IL-6 increased the level of nuclear factor-kappa B (NF-kB) phosphorylation. A pretreatment with SN50 or Bay11-7082 also blocked the IL-6-induced increase in -MG uptake. In conclusion, IL-6 increases the Na⁺/glucose cotransporter activity through reactive oxygen species (ROS), and its action in renal proximal tubule cells is associated with the STAT3, PI3K/Akt, MAPKs, and NF-kB signaling pathways.