Competing actions of type 1 angiotensin II receptors expressed on t lymphocytes and kidney epithelium during cisplatin-induced aki

Jiandong Zhang, Nathan P. Rudemiller, Mehul B. Patel, QingQing Wei, Norah S. Karlovich, Alexander D. Jeffs, Min Wu, Matthew A. Sparks, Jamie R. Privratsky, Marcela Herrera, Susan B. Gurley, Sergei A. Nedospasov, Steven D. Crowley

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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-a is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-a 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-a 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-a production induced by cisplatin. Finally, disrupting TNF-a production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-a levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatorymediators produced by renal parenchymal cellsmay 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.

Original languageEnglish (US)
Pages (from-to)2257-2264
Number of pages8
JournalJournal of the American Society of Nephrology
Issue number8
StatePublished - 2016

ASJC Scopus subject areas

  • Nephrology


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