title: Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.
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.
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Rudemiller
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Mehul B
authors.initials: MB
authors.lastname: Patel
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia; and.
authors.forename: QingQing
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Norah S
authors.initials: NS
authors.lastname: Karlovich
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Jeffs
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sparks
authors.affiliation: Department of Anesthesiology, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina;
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Privratsky
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Marcela
authors.initials: M
authors.lastname: Herrera
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Gurley
authors.affiliation: Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: Division of Nephrology, Department of Medicine and steven.d.crowley@duke.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Crowley
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage; D004848:Epithelium / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D044140:Receptor, Angiotensin, Type 1; D002945:Cisplatin
keywords: acute renal failure; angiotensin; cisplatin