Peroxisomal Proliferator-Activated Receptor-α Protects Renal Tubular Cells from Doxorubicin-Induced Apoptosis

Lin, Heng; Chun, Hou; Cheng, Ching Feng; Chiu, Ted H.; Hsu, Yung Ho; Sue, Yuh Mou; Chen, Tso Hsiao; Hou, Hsin Han; Chao, Ying‐Chi; Cheng, Tzu-Hurng; Chen, Cheng Hsien

doi:10.1124/mol.107.037523

Cited by 39 publications

(30 citation statements)

References 28 publications

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“…However, its clinical use is limited by its toxicity to multiple organs, including the heart and kidney (Okuda et al, 1986;Lin et al, 2007). In fact, the toxic mechanism of ADR and its prevention have been the focus of many previous investigations (Li et al, 2006;Granados-Principal et al, 2010;Papeta et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 2013

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Oxidative stress-induced podocyte injury is one of the major mechanisms underlying the initiation and progression of glomerulosclerosis. 59-AMP-activated protein kinase (AMPK), a serine/threonine kinase that senses intracellular energy status and maintains energy homeostasis, is reported to have antioxidative effects. However, little is known about its application and mechanism. In this study, we investigated whether and how AMPK affected oxidative podocyte injury induced by Adriamycin (ADR; Wako Pure Chemical, Osaka, Japan). Exposure of podocytes to ADR resulted in cell injury, which was preceded by increased reactive oxygen species (ROS) generation and P38 activation. Prevention of oxidative stress with the antioxidant Nacetyl-cysteine and glutathione or inhibition of P38 with SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] attenuated cell injury. Activation of AMPK with three structurally different AMPK activators also protected podocytes from ADR-elicited cell injury. This effect was associated with strong suppression of oxidative stress-sensitive kinase apoptosis signal-regulating kinase 1 (ASK1) and P38 without obvious influence on ROS level. Further analyses revealed that AMPK promoted thioredoxin (Trx) binding to ASK1. Consistently, AMPK potently suppressed the expression of thioredoxin-interacting protein (TXNIP), a negative regulator of Trx, whereas it significantly enhanced the activity of Trx reductases that convert oxidized Trx to reduced form. In further support of a key role of Trx, downregulation or inhibition of Trx exaggerated but downregulation of TXNIP attenuated the cell injury. These results indicate that AMPK prevents oxidative cell injury through Trx-mediated suppression of ASK1-P38 signaling pathway. Our findings thus provide novel mechanistic insights into the antioxidative actions of AMPK. AMPK could be developed as a novel therapeutic target for treatment of oxidative cell injury.

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Section: Discussionmentioning

confidence: 99%

“…ADR is also toxic to renal tubular epithelial cells (Lin et al, 2007). We therefore tested whether our findings in podocytes could also be applicable to tubular cells.…”

Section: And E)mentioning

confidence: 99%

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

et al. 2013

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“…52 Inhibition of NF-B in these circumstances promotes cell death; however, NF-B/RelA activation is involved in the apoptosis of podocytes in HIV-transgenic mice mediated by NF-B-dependent Fas and Fas ligand expression in nephrotoxin and ischemia-induced tubular cell apoptosis. 42,49,53,54 …”

Section: Regulation Of Transcriptionmentioning

confidence: 99%

NF-κB in Renal Inflammation

Sanz¹,

Sanchez-Niño²,

Ramos³

et al. 2010

Journal of the American Society of Nephrology

518

379

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“…Indeed, PPARs activation both stimulates the expression of the antioxidant enzyme superoxide dismutase and catalase, and regulates glutathione metabolism in several cell types (Lin et al 2007, Abdelmegeed et al 2009, Ibarra-Lara et al 2010. Activation of PPARa also regulates lipid peroxidation, a regulation evident in plasma and tissues in different pathologies and inflammatory conditions including the diabetic state (Inoue et al 1997, Anwer et al 2007, Belfort et al 2010.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is difficult to pinpoint the mechanism involved in the observed reduction of placental growth, our results suggest that it may be related to normalization of the production of NO, a pro-angiogenic and vasodilator agent (Dulak & Jozkowicz 2003, Valdes et al 2009, and not to changes in lipid concentrations and peroxidation, parameters that do not change when PPARa is activated in the fetuses. On the other hand, studies performed in trophoblasts and different cell types have shown that PPARs activation affects cell proliferation, differentiation, and apoptosis (Lin et al 2007, Barak et al 2008, Fournier et al 2008, Parast et al 2009, Arck et al 2010, Benameur et al 2010, suggesting that there may be many pathways related to placental growth that could be regulated by activating fetal PPARa that deserves further study.…”

Section: Discussionmentioning

confidence: 99%

PPARα agonists regulate lipid metabolism and nitric oxide production and prevent placental overgrowth in term placentas from diabetic rats

Martínez¹,

Kurtz²,

Capobianco³

et al. 2011

Journal of Molecular Endocrinology

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Maternal diabetes impairs fetoplacental metabolism and growth. Peroxisome proliferator-activated receptor a (PPARa) is a nuclear receptor capable of regulating lipid metabolism and inflammatory pathways. In this study, we analyzed whether placental and fetal PPARa activation regulates lipid metabolism and nitric oxide (NO) production in term placentas from diabetic rats. Diabetes was induced by neonatal streptozotocin administration. On day 21 of pregnancy, placentas from control and diabetic rats were cultured in the presence of PPARa agonists (clofibrate and leukotriene B 4 (LTB 4 )) for further evaluation of levels, synthesis, and peroxidation of lipids as well as NO production. Besides, on days 19, 20, and 21 of gestation, fetuses were injected with LTB 4 , and the placentas were explanted on day 21 of gestation for evaluation of placental weight and concentrations of placental lipids, lipoperoxides, and NO metabolites. We found that placentas from diabetic rats showed reduced PPARa concentrations. They presented no lipid overaccumulation but reduced lipid synthesis, parameters negatively regulated by PPARa activators. Lipid peroxidation and NO production, increased in placentas from diabetic rats, were negatively regulated by PPARa activators. Fetal PPARa activation in diabetic rats does not change placental lipid concentrations but reduced placental weight and NO production. In conclusion, PPARa activators regulate lipid metabolism and NO production in term placentas from diabetic rats, an activation that regulates placental growth and can partly be exerted by the developing fetus.

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Peroxisomal Proliferator-Activated Receptor-α Protects Renal Tubular Cells from Doxorubicin-Induced Apoptosis

Cited by 39 publications

References 28 publications

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

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

NF-κB in Renal Inflammation

PPARα agonists regulate lipid metabolism and nitric oxide production and prevent placental overgrowth in term placentas from diabetic rats

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