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Activation of the Signal Transducer and Activator of Transcription Signaling Pathway in Renal Proximal Tubular Cells by Albumin

Hideaki Nakajima^*, Masaru Takenaka^*,, Jun-Ya Kaimori^*, Takayuki Hamano^*, Hirotsugu Iwatani^*, Takeshi Sugaya, Takahito Ito^*, Masatsugu Hori^* and Enyu Imai^*

*Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Center of Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Ibaraki, and Graduate School of Life Science, Kobe Women’s University, Kobe, Japan.

Correspondence to: Dr. Masaru Takenaka, Department of Internal Medicine and Therapeutics (Box A8), Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan. Phone: +81787314416; Fax: +81787325161; E-mail: masaru{at}suma.kobe-wu.ac.jp

ABSTRACT. 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-. 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-–inducible proteins are synthesized through IFN-–independent activation of STAT signaling.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673