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Article: Activation of p53 promotes renal injury in acute aristolochic acid nephropathy

TitleActivation of p53 promotes renal injury in acute aristolochic acid nephropathy
Authors
Issue Date2010
PublisherAmerican Society of Nephrology. The Journal's web site is located at http://www.jasn.org
Citation
Journal of the American Society of Nephrology, 2010, v. 21 n. 1, p. 31-41 How to Cite?
AbstractIngestion of aristolochic acid (AA) can cause AA nephropathy (AAN), in which excessive death of tubular epithelial cells (TECs) characterize the acute phase. AA forms adducts with DNA, which may lead to TEC apoptosis via p53-mediated signaling. We tested this hypothesis both by studying p53-deficient mice and by blocking p53 in TECs with its inhibitor pifithrin-alpha. AA induced acute AAN in wild-type mice, resulting in massive apoptotic and necrotic TEC death and acute renal failure; p53 deficiency or pharmacologic inhibition attenuated this injury. In vitro, AA induced apoptotic and necrotic death of TEC in a time- and dosage-dependent manner, with apoptosis marked by a 10-fold increase in cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling-positive/Annexin V-positive propidium iodide-negative TECs (all P < 0.001). AA induced dephosphorylation of STAT3 and the subsequent activation of p53 and TEC apoptosis. In contrast, overexpression of STAT3, p53 inhibition, or p53 knockdown with small interfering RNA all attenuated AA-induced TEC apoptosis. Taken together, these results suggest that AA induces TEC death via apoptosis by dephosphorylation of STAT3 and posttranslational activation of p53, supporting the hypothesis that p53 promotes renal injury in acute AAN.
Persistent Identifierhttp://hdl.handle.net/10722/224778
ISSN
2015 Impact Factor: 8.491
2015 SCImago Journal Rankings: 4.699
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorZhou, L-
dc.contributor.authorFu, P-
dc.contributor.authorHuang, XR-
dc.contributor.authorLiu, F-
dc.contributor.authorLai, KN-
dc.contributor.authorLan, HY-
dc.date.accessioned2016-04-14T08:34:42Z-
dc.date.available2016-04-14T08:34:42Z-
dc.date.issued2010-
dc.identifier.citationJournal of the American Society of Nephrology, 2010, v. 21 n. 1, p. 31-41-
dc.identifier.issn1046-6673-
dc.identifier.urihttp://hdl.handle.net/10722/224778-
dc.description.abstractIngestion of aristolochic acid (AA) can cause AA nephropathy (AAN), in which excessive death of tubular epithelial cells (TECs) characterize the acute phase. AA forms adducts with DNA, which may lead to TEC apoptosis via p53-mediated signaling. We tested this hypothesis both by studying p53-deficient mice and by blocking p53 in TECs with its inhibitor pifithrin-alpha. AA induced acute AAN in wild-type mice, resulting in massive apoptotic and necrotic TEC death and acute renal failure; p53 deficiency or pharmacologic inhibition attenuated this injury. In vitro, AA induced apoptotic and necrotic death of TEC in a time- and dosage-dependent manner, with apoptosis marked by a 10-fold increase in cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling-positive/Annexin V-positive propidium iodide-negative TECs (all P < 0.001). AA induced dephosphorylation of STAT3 and the subsequent activation of p53 and TEC apoptosis. In contrast, overexpression of STAT3, p53 inhibition, or p53 knockdown with small interfering RNA all attenuated AA-induced TEC apoptosis. Taken together, these results suggest that AA induces TEC death via apoptosis by dephosphorylation of STAT3 and posttranslational activation of p53, supporting the hypothesis that p53 promotes renal injury in acute AAN.-
dc.languageeng-
dc.publisherAmerican Society of Nephrology. The Journal's web site is located at http://www.jasn.org-
dc.relation.ispartofJournal of the American Society of Nephrology-
dc.titleActivation of p53 promotes renal injury in acute aristolochic acid nephropathy-
dc.typeArticle-
dc.identifier.emailZhou, L: zhou1008@hkusua.hku.hk-
dc.identifier.emailLiu, F: ltight@163.com-
dc.identifier.emailLai, KN: knlai@hku.hk-
dc.identifier.emailLan, HY: hylan@hku.hk-
dc.identifier.authorityLai, KN=rp00324-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1681/ASN.2008111133-
dc.identifier.pmid19892935-
dc.identifier.pmcidPMC2799275-
dc.identifier.hkuros180819-
dc.identifier.volume21-
dc.identifier.issue1-
dc.identifier.spage31-
dc.identifier.epage41-
dc.publisher.placeUnited States-

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