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Table of Contents
Vol. 121, No. 1-2, 2012
Issue release date: December 2012
Section title: Original Paper
Nephron Exp Nephrol 2012;121:e38–e48
(DOI:10.1159/000342802)

Activation of AMP-Activated Protein Kinase Inhibits Albumin-Induced Endoplasmic Reticulum Stress and Apoptosis through Inhibition of Reactive Oxygen Species

Lee E.K.a · Jeong J.U.b · Chang J.W.b · Yang W.S.b · Kim S.B.b · Park S.K.b · Park J.S.b · Lee S.K.b
aDepartment of Internal Medicine, Dankook University Hospital, Cheonan, and bDepartment of Internal Medicine, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: February 03, 2012
Accepted: August 14, 2012
Published online: October 25, 2012
Issue release date: December 2012

Number of Print Pages: 11
Number of Figures: 7
Number of Tables: 0

ISSN: (Print)
eISSN: 1660-2129 (Online)

For additional information: http://www.karger.com/NEE

Abstract

Background: Endoplasmic reticulum (ER) stress induced by urinary albumin plays an important role in tubulointerstitial injury. We have shown that albumin-induced ER stress is regulated through reactive oxygen species (ROS)-c-Src kinase-mTOR signaling pathways. We postulated that peroxisome proliferator-activated receptor-γ (PPAR-γ) might also act as an upstream signaling molecule between c-Src kinase and mTOR. It has been suggested that AMP-activated protein kinase (AMPK) is involved in attenuation of ER stress. We examined whether and how activation of AMPK suppressed the albumin-induced ER stress and apoptosis in tubular epithelial cells. Method: HK-2 cells, a proximal tubular cell line, were used. Protein expressions were measured by Western blot analysis. Intracellular ROS and apoptosis were analyzed by flow cytometry. Results: Albumin-induced PPAR-γ expression and PPAR-γ inhibitor (GW9662) suppressed the albumin-induced ER stress. c-Src kinase inhibitor and GW9662 reduced the albumin-induced PPAR-γ and mTOR, respectively. Metformin (the best known clinical activator of AMPK) and another AMPK activator (AICAR) suppressed the albumin-induced ER stress via inhibition of ROS through induction of endogenous antioxidant thioredoxin. AMPK inhibitor blocked the effect of metformin and AICAR. Our in vivo animal study showed that metformin reduced the renal cortical expression of ER stress protein (GRP78) in protein-overload proteinuria rats. Metformin also reduced the caspase 3-dependent apoptosis induced by albumin. Conclusion: PPAR-γ was involved in albumin-induced ER stress as an upstream signaling molecule between c-Src kinase and mTOR. AMPK activation might be beneficial in attenuating the tubulointerstitial injury induced by albumin.

© 2012 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: February 03, 2012
Accepted: August 14, 2012
Published online: October 25, 2012
Issue release date: December 2012

Number of Print Pages: 11
Number of Figures: 7
Number of Tables: 0

ISSN: (Print)
eISSN: 1660-2129 (Online)

For additional information: http://www.karger.com/NEE


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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