NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury

Yan, Qiaojing; Gao, Kun; Chi, Yuan; Li, Kai; Zhu, Ying; Wan, Yi‐Gang; Sun, Wei; Matsue, Hiroyuki; Kitamura, Masanori; Yao, Jian

doi:10.1016/j.freeradbiomed.2012.07.012

Cited by 32 publications

(51 citation statements)

References 54 publications

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“…Among the many kinases activated by ROS, mitogen-activated protein kinases, P38, and c-Jun NH 2 -terminal kinase have been shown to play a key role in oxidative cell injury. Previous studies in podocytes have demonstrated that suppression of P38 attenuates podocyte injury in rat puromycin aminonucleoside nephropathy and mouse ADR nephropathy (Koshikawa et al, 2005;Yan et al, 2012). Consistent with these previous reports, we confirmed the mediating role of P38.…”

Section: Ampk Attenuates Oxidative Cell Injurysupporting

confidence: 92%

“…3A). As an oxidative stress-sensitive kinase, P38 has been reported to mediate oxidative cell injury both in vivo and in vitro (Koshikawa et al, 2005;Yan et al, 2012). Here, we also observed that inhibition of P38 with SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] significantly attenuated the loss of cell viability induced by ADR (Fig.…”

Section: And E)supporting

confidence: 74%

“…We have also tried to confirm the role of AMPK by using genetic approaches. Unfortunately, podocytes we used were difficult to be transfected, which we described in our previous report (Yan et al, 2012).…”

Section: Ampk Attenuates Oxidative Cell Injurymentioning

confidence: 98%

“…NRK-E52 cells were exposed to stimuli for 24 hours and stained with propidium iodide (PI) for 5 minutes according to the protocol provided by the manufacturer (BioVision Research, Mountain View, CA) (Yan et al, 2012). After that, they were subjected to fluorescence microscopy examination.…”

Section: Detection Of Omentioning

confidence: 99%

“…Western blot analysis was performed by use of the enhanced chemiluminescence system Yan et al, 2012). Briefly, extracted cellular proteins were separated by 10% or 12% SDS-polyacrylamide gels and electrotransferred onto polyvinylidene difluoride membranes.…”

Section: Detection Of Omentioning

confidence: 99%

See 4 more Smart Citations

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: Ampk Attenuates Oxidative Cell Injurysupporting

confidence: 92%

Section: And E)supporting

confidence: 74%

Section: Ampk Attenuates Oxidative Cell Injurymentioning

confidence: 98%

Section: Detection Of Omentioning

confidence: 99%

Section: Detection Of Omentioning

confidence: 99%

See 3 more Smart Citations

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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Mind the gap: connexins and cell–cell communication in the diabetic kidney

2014

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Connexins, assembled as a hexameric connexon, form a transmembrane hemichannel that provides a conduit for paracrine signalling of small molecules and ions to regulate the activity and function of adjacent cells. When hemichannels align and associate with similar channels on opposing cells, they form a continuous aqueous pore or gap junction, allowing the direct transmission of metabolic and electrical signals between coupled cells. Regulation of gap junction synthesis and channel activity is critical for cell function, and a number of diseases can be attributed to changes in the expression/function of these important proteins. Diabetic nephropathy is associated with several complex metabolic and inflammatory responses characterised by defects at the molecular, cellular and tissue level. In both type 1 and type 2 diabetes, glycaemic injury of the kidney is the leading cause of end-stage renal failure, a consequence of multiple aetiologies, including increased deposition of extracellular matrix, glomerular hyperfiltration, albuminuria and tubulointerstitial fibrosis. In diabetic nephropathy, loss of connexin mediated cell-cell communication within the nephron may represent an early sign of disease; however, our current knowledge of the role of connexins in the diabetic kidney is sparse. This review highlights recent evidence demonstrating that maintained connexin-mediated cell-cell communication could benefit region-specific renal function in diabetic nephropathy and suggests that these proteins should be viewed as a tantalising novel target for therapeutic intervention.

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Upregulation of connexin43 contributes to PX-12-induced oxidative cell death

Gao

Chi

et al. 2015

Tumor Biol.

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Thioredoxin (Trx) is a small redox protein that underlies aggressive tumor growth and resistance to chemotherapy. Inhibition of Trx with the chemical inhibitor PX-12 suppresses tumor growth and induces cell apoptosis. Currently, the mechanism underlying the therapeutic actions of PX-12 and the molecules influencing cell susceptibility to PX-12 are incompletely understood. Given that connexin43 (Cx43), a tumor suppressor, regulates tumor cell susceptibility to chemotherapy, we examined the possible involvement of Cx43 in PX-12-induced cell death. Exposure of cells to PX-12 led to a loss of cell viability, which was associated with the activation of oxidative sensitive c-Jun N-terminal kinase (JNK). Inhibition of JNK or supplement of cells with anti-oxidants prevented the cell-killing action of PX-12. The forced expression of Cx43 in normal and tumor cells increased cell sensitivity to PX-12-induced JNK activation and cell death. In contrast, the downregulation of Cx43 with siRNA or the suppression of gap junctions with chemical inhibitors attenuated JNK activation and enhanced cell resistance to PX-12. Further analysis revealed that PX-12 at low concentrations induced a JNK-dependent elevation in the Cx43 protein, which was also preventable by supplementing the cells with anti-oxidants. Our results thus indicate that Cx43 is a determinant in the regulation of cell susceptibility to PX-12 and that the upregulation of Cx43 may be an additional mechanism by which PX-12 exerts its anti-tumor actions.

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NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury

Cited by 32 publications

References 54 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

Mind the gap: connexins and cell–cell communication in the diabetic kidney

Upregulation of connexin43 contributes to PX-12-induced oxidative cell death

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