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Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI.

Publication ,  Journal Article
Ren, J; Liu, K; Wu, B; Lu, X; Sun, L; Privratsky, JR; Xing, C; Robson, MJ; Mao, H; Blakely, RD; Abe, K; Souma, T; Crowley, SD
Published in: J Am Soc Nephrol
October 1, 2023

SIGNIFICANCE STATEMENT: Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. However, blockade of IL-1 signaling in AKI has not consistently demonstrated kidney protection. The current murine experiments show that IL-1R1 activation in the proximal tubule exacerbates toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorates AKI by restoring VEGFA-dependent endothelial cell viability. Using this information, future delivery strategies can maximize the protective effects of blocking IL-1R1 while mitigating unwanted actions of IL-1R1 manipulation. BACKGROUND: Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. METHODS: To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. RESULTS: scRNA-seq analyses demonstrated robust IL-1 expression in myeloid cell populations and low-level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorated aristolochic acid-induced AKI by restoring VEGFA-dependent endothelial cell viability and density. CONCLUSIONS: These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI after toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.

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Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

October 1, 2023

Volume

34

Issue

10

Start / End Page

1629 / 1646

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Receptors, Interleukin-1
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Interleukin-1
  • Humans
  • Endothelium
  • Endothelial Cells
  • Apolipoproteins M
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ren, J., Liu, K., Wu, B., Lu, X., Sun, L., Privratsky, J. R., … Crowley, S. D. (2023). Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI. J Am Soc Nephrol, 34(10), 1629–1646. https://doi.org/10.1681/ASN.0000000000000191
Ren, Jiafa, Kang Liu, Buyun Wu, Xiaohan Lu, Lianqin Sun, Jamie R. Privratsky, Changying Xing, et al. “Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI.J Am Soc Nephrol 34, no. 10 (October 1, 2023): 1629–46. https://doi.org/10.1681/ASN.0000000000000191.
Ren J, Liu K, Wu B, Lu X, Sun L, Privratsky JR, et al. Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI. J Am Soc Nephrol. 2023 Oct 1;34(10):1629–46.
Ren, Jiafa, et al. “Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI.J Am Soc Nephrol, vol. 34, no. 10, Oct. 2023, pp. 1629–46. Pubmed, doi:10.1681/ASN.0000000000000191.
Ren J, Liu K, Wu B, Lu X, Sun L, Privratsky JR, Xing C, Robson MJ, Mao H, Blakely RD, Abe K, Souma T, Crowley SD. Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI. J Am Soc Nephrol. 2023 Oct 1;34(10):1629–1646.

Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

October 1, 2023

Volume

34

Issue

10

Start / End Page

1629 / 1646

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Receptors, Interleukin-1
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Interleukin-1
  • Humans
  • Endothelium
  • Endothelial Cells
  • Apolipoproteins M