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

Abstract

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.

Interleukin‐6 promotes 2‐deoxyglucose uptake through p44/42 MAPKs activation via Ca2+/PKC and EGF receptor in primary cultured chicken hepatocytes

“…Interestingly, IL-6 mediates glucose incorporation into glycogen, glucose uptake, lactate production, and fatty acid uptake, and oxidation (Al-Khalili et al, 2006). IL-6 has also been shown to regulate several transporters such as GLUTs and SGLTs (Stouthard et al, 1996;Shikhman et al, 2001;Lee et al, 2007). These observations suggest that IL-6 is required for maintenance of normal glucose homeostasis and whole body metabolism.…”

“…Signal transduction by the IL-6 family of cytokines involves the activation of two major pathways: the JAK/STAT and MAPK pathways . Moreover, IL-6 activates PI3K/ Akt, sphingosine kinase (SPHK) (Li et al, 2007), p38 MAKP, JNK, and nuclear factor-kappa B (NF-kB) (Lee et al, 2007). Interestingly, these signals are involved in GLUT promoter-related genes.…”

Effect of leukotriene D4 on mouse embryonic stem cell migration and proliferation: Involvement of PI3K/Akt as well as GSK‐3β/β‐catenin signaling pathways

“…influx and the Akt pathway [Kim et al, 2009]. It has been reported that these PI3K/Akt cascades activate two potentially independent pathways; one regulated by Ras signaling and the other regulated by the STAT3-containing complex [Hsu et al, 2004;Lee et al, 2007;Lu et al, 2008]. These results imply that the LTD 4 -induced PI3K/Akt pathway might play a critical role in ES cells via STAT3 activation as well as via an increase of intracellular Ca 2þ concentration.…”

The Role of STAT3 Activation in Glomerulonephritis

“…Transfection of glomerular mesangial cells with JAK2 antisense oligonucleotides blocks angiotensin II-induced growth and collagen IV synthesis under both normal and high glucose conditions. In renal proximal tubule cells, IL-6 increases phosphorylation of STAT3, phosphoinositide-3 kinase (PI3K)/Akt, MAPKs, and NF-κB (Lee et al, 2007). IL-6 also stimulates -methyl-D-[ 14 C]glucopyranoside uptake, which is indicative of active transport in renal proximal tubule cells.…”