The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes
Open accessAbstract
Diabetes and high glucose (HG) increase the generation of NADPH oxidase-derived reactive oxygen species and induce apoptosis of glomerular epithelial cells (podocytes). Loss of podocytes contributes to albuminuria, a major risk factor for progression of kidney disease. Here, we show that HG inactivates AMP-activated protein kinase (AMPK), up-regulates Nox4, enhances NADPH oxidase activity, and induces podocyte apoptosis. Activation of AMPK blocked HG-induced expression of Nox4, NADPH oxidase activity, and apoptosis. We also identified the tumor suppressor protein p53 as a mediator of podocyte apoptosis in cells exposed to HG. Inactivation of AMPK by HG up-regulated the expression and phosphorylation of p53, and p53 acted downstream of Nox4. To investigate the mechanism of podocyte apoptosis in vivo, we used OVE26 mice, a model of type 1 diabetes. Glomeruli isolated from these mice showed decreased phosphorylation of AMPK and enhanced expression of Nox4 and p53. Pharmacologic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-riboside in OVE26 mice attenuated Nox4 and p53 expression. Administration of 5-aminoimidazole-4-carboxamide-1-riboside also prevented renal hypertrophy, glomerular basement thickening, foot process effacement, and podocyte loss, resulting in marked reduction in albuminuria. Our results uncover a novel function of AMPK that integrates metabolic input to Nox4 and provide new insight for activation of p53 to induce podocyte apoptosis. The data indicate the potential therapeutic utility of AMPK activators to block Nox4 and reactive oxygen species generation and to reduce urinary albumin excretion in type 1 diabetes.
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Cites
Biochemistry and molecular cell biology of diabetic complications
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Blinded by the Light: The Growing Complexity of p53
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Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis
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p53 Has a Direct Apoptogenic Role at the Mitochondria
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AMP-activated protein kinase induces a p53-dependent metabolic checkpoint
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p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa
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Cited by
Molecular mechanisms of diabetic kidney disease
Reidy, K., Kang, H. M., Hostetter, T., & Susztak, K. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72271 · Cited by 909
NADPH Oxidases (NOX): An Overview from Discovery, Molecular Mechanisms to Physiology and Pathology
Vermot, A., Petit-Härtlein, I., Smith, S. M. E., & Fieschi, F. (2021) · Antioxidants · doi:10.3390/antiox10060890 · Cited by 766
Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance
Hecker, L., Logsdon, N. J., Kurundkar, D., Kurundkar, A., Bernard, K., Hock, T., Meldrum, E., Sanders, Y. Y., & Thannickal, V. J. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008182 · Cited by 686
Diabetes and Kidney Disease: Role of Oxidative Stress
Jha, J. C., Banal, C., Chow, B. S. M., Cooper, M. E., & Jandeleit-Dahm, K. (2016) · Antioxidants & Redox Signaling · doi:10.1089/ars.2016.6664 · Cited by 660
Current knowledge and pharmacological profile of berberine: An update
Kumar, A., Ekavali, Chopra, K., Mukherjee, M., Pottabathini, R., & Dhull, D. K. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.05.068 · Cited by 530
Metadata
- Authors
- Eid, A. A., Ford, B. M., Block, K., Kasinath, B. S., Gorin, Y., Ghosh-Choudhury, G., Barnes, J. L., & Abboud, H. E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 285
- Issue
- 48
- Pages
- 37503-37512
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2049368067
- Cited by
- 254
- References
- 65
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes. https://app.cochat.ai/papers/10.1074/jbc.m110.136796
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- Eid, A. A., Ford, B. M., Block, K., Kasinath, B. S., Gorin, Y., Ghosh-Choudhury, G., Barnes, J. L., & Abboud, H. E. (2010). AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m110.136796
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