Activation of the signal transducer and activator of transcription signaling pathway in renal proximal tubular cells by albumin.
Renal proximal tubular cells activated by reabsorption of protein are thought to play significant roles in the progression of kidney diseases. It was hypothesized that the signal transducer and activator of transcription (STAT) proteins may be activated by proteinuria in proximal tubular cells. To test this hypothesis, murine proximal tubular cells were treated with albumin (30 mg/ml medium) for various lengths of time. The results showed that albumin could activate Stat1 and Stat5 within 15 min in proximal tubular cells. The activation of STATs was mediated mostly by Jak2 and required no protein synthesis. In addition, activation of Stat1 occurred even after neutralization of IFN-gamma. The activation of STATs was inhibited by N-acetyl-L-cysteine, a precursor of glutathione and a reactive oxygen species (ROS) scavenger, and fluorescence-activated cell sorter analysis showed upregulation of intracellular ROS after albumin overloading, suggesting that albumin per se could generate ROS in proximal tubular cells. The activation of STATs occurred by way of the ROS generating system, and especially through the membrane-bound NADPH oxidase system. Reduced activities of glutathione peroxidase and catalase could also be responsible for the accumulation of intracellular ROS. Hence, not only the ROS generating system, but also the ROS scavenging system may contribute to the induction of ROS by albumin. These findings support the hypothesis that proximal tubular cells are activated and generate ROS by reabsorption of abundant urinary proteins filtered through the glomerular capillaries, and as a consequence, various IFN-gamma-inducible proteins are synthesized through IFN-gamma-independent activation of STAT signaling.
Nakajima
Hideaki
H
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
Takenaka
Masaru
M
Kaimori
Jun-Ya
JY
Hamano
Takayuki
T
Iwatani
Hirotsugu
H
Sugaya
Takeshi
T
Ito
Takahito
T
Hori
Masatsugu
M
Imai
Enyu
E
D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000502:physiology*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D053614:Janus Kinase 2; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D010084:Oxidation-Reduction; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects* / Q000502:physiology*
D000418:Albumins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D005978:Glutathione