Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.
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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.
Published Version (Please cite this version)10.1681/ASN.2015060683
Publication InfoCrowley, Steven Daniel; Gurley, SB; Herrera, M; Jeffs, AD; Karlovich, NS; Nedospasov, SA; ... Zhang, J (2016). Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI. J Am Soc Nephrol, 27(8). pp. 2257-2264. 10.1681/ASN.2015060683. Retrieved from http://hdl.handle.net/10161/11963.
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Associate Professor of Medicine
Our laboratory explores the contribution of the immune system and inflammatory mediators to the progression of target organ damage in the setting of cardiovascular disease. We are pursuing several related projects in this field:(1) The actions of type 1 angiotensin receptors on specific immune cell populations in hypertension, target organ damage, and tissue fibrosis.(2) Cell-specific actions of inflammatory cytokines in regulating blood pressure and end-organ injury.(3) Mechan
Assistant Professor of Medicine
My lab is interested in understanding how both the renin angiotensin and prostanoid systems regulate blood pressure by altering blood flow to the kidney. My lab utilizes a combination of physiologic and molecular techniques in genetically modified mice to probe questions about how changes in the micro circulation in the kidney alter sodium excretion. The overarching goal of this research is to identify novel mechanisms to target drug therapy for patients with hypertension. My research is fund
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