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Kidney Week

Abstract: FR-PO164

IL-22 Promotes Kidney Injury Through Activation of DNA Damage Response

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Taguchi, Kensei, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Sugahara, Sho, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Elias, Bertha C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Brooks, Craig R., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Acute kidney injury (AKI) occurs in up to 20% of hospitalized patients. Increased production of proinflammatory cytokine both predicts mortality in patients with AKI and worsens outcomes. Interleukin-22 (IL-22) is a member of IL-10 family whose receptor, (IL-22RA1), is expressed exclusively on epithelial or endothelial cells. In the kidney, IL-22RA1 expression is limited to proximal tubule cells (PTCs). Recently, IL-22 has shown to regulate the DNA damage response (DDR). The DDR is known to act as a double-edged-sword in AKI. While DNA repair is necessary for recovery from AKI, overactivation of the DDR is a major contributing factor to cell death and worsens kidney injury.

Methods

1; Nephrotoxic AKI was induced by repeated doses of aristolochic acid (AA) or single dose of cisplatin in 8 to 12-week-old male wild-type (WT) and IL-22 globally knockout mice. 2; To investigate kidney specific effect of IL-22, nephrotoxic AKI was induced in IL-22RA1 flox/flox; Six2-cre (IL-22RA1ΔPT) and IL-22RA1 flox/flox. 3; S3I-201, an inhibitor of STAT3, was intraperitoneally injected into cisplatin-treated WT mice.

Results

IL-22 is upregulated ~500 fold in the urine of cisplatin treated mice with no increase in plasma levels. IL-22RA1 is predominantly expressed in S3 segment of PTCs in basal conditions and expands to S1-S2 segments in response to AKI. Deletion of IL-22 or its receptor nearly completely ameliorates kidney injury induced by cisplatin or AA. Analysis of the kidney tissue reveals reduced apoptosis and kidney injury markers. DDR activation, as measured by phosphorylation of p53 and Ataxia telangiectasia mutated (ATM), is reduced in both IL-22 knockouts and IL-22RA1ΔPT. Mechanistically, IL-22 induces activation of STAT3 to trigger the DDR and subsequent apoptosis, which was blocked by STAT3 inhibitor S3I-201 in vitro and in vivo.

Conclusion

Our results demonstrate that in the absence of IL-22 or its receptor, the nephrotoxic effects of cisplatin or AA are ameliorated. The engagement of IL-22 to IL-22RA1 activates STAT3 to induce DDR signaling, p53 and ATM, resulting in increased apoptotic. Thus, targeting IL-22 can reduce the negative effects of STAT3, p53, and ATM activation in AKI, without interfering with their basal homeostatic functions, providing a safe alternative to targeting these pathways directly.