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Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.

dc.contributor.author Crowley, Steven Daniel
dc.contributor.author Gurley, SB
dc.contributor.author Herrera, M
dc.contributor.author Jeffs, AD
dc.contributor.author Karlovich, NS
dc.contributor.author Nedospasov, SA
dc.contributor.author Patel, MB
dc.contributor.author Privratsky, JR
dc.contributor.author Rudemiller, Nathan P
dc.contributor.author Sparks, Matthew A
dc.contributor.author Wei, Q
dc.contributor.author Wu, M
dc.contributor.author Zhang, J
dc.coverage.spatial United States
dc.date.accessioned 2016-05-02T20:40:37Z
dc.date.issued 2016-08
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/26744488
dc.identifier ASN.2015060683
dc.identifier.uri http://hdl.handle.net/10161/11963
dc.description.abstract Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT1) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-α is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-α is suppressed or enhanced by AT1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-α levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-α production induced by cisplatin. Finally, disrupting TNF-α production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-α levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.
dc.language eng
dc.relation.ispartof J Am Soc Nephrol
dc.relation.isversionof 10.1681/ASN.2015060683
dc.subject acute renal failure
dc.subject angiotensin
dc.subject cisplatin
dc.title Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/26744488
pubs.begin-page 2257
pubs.end-page 2264
pubs.issue 8
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Nephrology
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 27
dc.identifier.eissn 1533-3450


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