5′-AMP-Activated Protein Kinase Attenuates Adriamycin-Induced Oxidative Podocyte Injury through Thioredoxin-Mediated Suppression of the Apoptosis Signal-Regulating Kinase 1–P38 Signaling Pathway

• DOI: 10.1124/mol.113.089458
• Publication Date: 2014-01-02T06:23:45Z
• Authors: Kun Gao; Yuan Chi; Wei Sun; Masayuki Takeda; Jian Yao
• Keywords: ASK1

Oxidative stress–induced podocyte injury is one of the major mechanisms underlying initiation and progression glomerulosclerosis. 5′-AMP-activated protein kinase (AMPK), a serine/threonine that senses intracellular energy status maintains homeostasis, reported to have antioxidative effects. However, little known about its application mechanism. In this study, we investigated whether how AMPK affected oxidative induced by Adriamycin (ADR; Wako Pure Chemical, Osaka, Japan). Exposure podocytes ADR resulted in cell injury, which was preceded increased reactive oxygen species (ROS) generation P38 activation. Prevention stress with antioxidant <i>N</i>-acetyl-cysteine glutathione or inhibition SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1<i>H</i>-imidazole] attenuated injury. Activation three structurally different activators also protected from ADR-elicited This effect associated strong suppression stress-sensitive apoptosis signal-regulating 1 (ASK1) without obvious influence on ROS level. Further analyses revealed promoted thioredoxin (Trx) binding ASK1. Consistently, potently suppressed expression thioredoxin-interacting (TXNIP), negative regulator Trx, whereas it significantly enhanced activity Trx reductases convert oxidized reduced form. further support key role downregulation exaggerated but TXNIP These results indicate prevents through Trx-mediated ASK1-P38 signaling pathway. Our findings thus provide novel mechanistic insights into actions AMPK. could be developed as therapeutic target for treatment