Interleukin 1 receptor (IL-1R1) activation exacerbates toxin-induced acute kidney injury

Jamie R. Privratsky, Jiandong Zhang, Xiaohan Lu, Nathan Rudemiller, QingQing Wei, Yen Rei Yu, Michael D. Gunn, Steven D. Crowley

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Acute kidney injury (AKI) is a leading cause of morbidity and mortality. Drug-induced/toxic AKI can be caused by a number of therapeutic agents. Cisplatin is an effective chemotherapeutic agent whose administration is limited by significant nephrotoxicity. Therapies to prevent cisplatin-induced AKI are lacking. Although tumor necrosis factor-α (TNF) plays a key role in the pathogenesis of cisplatin nephrotoxicity, the innate immune signaling pathways that trigger TNF generation in this context require elucidation. In this regard, sterile injury triggers the release and activation of both isoforms of interleukin(IL)-1, IL-1α and IL-1β. In turn, stimulation of the interleukin-1 receptor (IL-1R1) by these ligands engages a proinflammatory signaling cascade that induces TNF induction. We therefore hypothesized that IL-1R1 activation exacerbates cisplatin-induced AKI by inducing TNF production, thereby augmenting inflammatory signals between kidney parenchymal cells and infiltrating myeloid cells. IL-1R1+/+ (WT) and IL-1R1-/-(KO) mice were subjected to cisplatin-induced AKI. Compared with WT mice, IL-1R1 KO mice had attenuated AKI as measured by serum creatinine and BUN, renal NGAL mRNA levels, and blinded histological analysis of kidney pathology. In the cisplatin-injured kidney, IL-1R1 KO mice had diminished levels of whole kidney TNF, and fewer Ly6G-expressing neutrophils. In addition, an unbiased machine learning analysis of intrarenal immune cells revealed a diminished number of CD11bint/CD11cint myeloid cells in IL-1R1 KO injured kidneys compared with IL-1R1 WT kidneys. Following cisplatin, IL-1R1 KO kidneys, compared with WTs, had fewer TNF-producing: macrophages, CD11bint/CD11cint cells, and neutrophils, consistent with an effect of IL-1R1 to polarize intrarenal myeloid cells toward a proinflammatory phenotype. Interruption of IL-1-dependent signaling pathways warrants further evaluation to decrease nephrotoxicity during cisplatin therapy.

Original languageEnglish (US)
Pages (from-to)F682-F691
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number3
DOIs
StatePublished - Sep 6 2018

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Interleukin-1 Receptors
Interleukins
Acute Kidney Injury
Cisplatin
Kidney
Tumor Necrosis Factor-alpha
Interleukin-1
Myeloid Cells
Neutrophils
Poisons
Blood Urea Nitrogen
Creatinine
Protein Isoforms
Therapeutics
Macrophages
Pathology
Ligands
Morbidity
Phenotype
Messenger RNA

Keywords

  • Acute kidney injury
  • Interleukin-1
  • Myeloid

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Interleukin 1 receptor (IL-1R1) activation exacerbates toxin-induced acute kidney injury. / Privratsky, Jamie R.; Zhang, Jiandong; Lu, Xiaohan; Rudemiller, Nathan; Wei, QingQing; Yu, Yen Rei; Gunn, Michael D.; Crowley, Steven D.

In: American Journal of Physiology - Renal Physiology, Vol. 315, No. 3, 06.09.2018, p. F682-F691.

Research output: Contribution to journalArticle

Privratsky, Jamie R. ; Zhang, Jiandong ; Lu, Xiaohan ; Rudemiller, Nathan ; Wei, QingQing ; Yu, Yen Rei ; Gunn, Michael D. ; Crowley, Steven D. / Interleukin 1 receptor (IL-1R1) activation exacerbates toxin-induced acute kidney injury. In: American Journal of Physiology - Renal Physiology. 2018 ; Vol. 315, No. 3. pp. F682-F691.
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