IL-22 Secreted from Proximal Tubule Cells Regulates Cell Fate During AKI
- AKI: Mechanisms - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Sugahara, Sho, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Taguchi, Kensei, Kurume Daigaku Igakubu Daigakuin Igaku Kenkyuka, Kurume, Fukuoka, Japan
- Elias, Bertha C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Canaud, Guillaume, Universite Paris Cite UFR de Medecine, Paris, Île-de-France, France
- Brooks, Craig R., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Acute kidney injury (AKI) occurs in ~13% of hospitalized patients and is associated with a fourfold increase in mortality. Proximal tubule cells (PTCs) are key to the outcome of AKI as they are the most sensitive cells to AKI and respond by secreting a number of inflammatory and/or pro-reparative cytokines. Interleukin-22 (IL-22) is an IL-10 family cytokine produced after tissue injury. IL-22 is secreted exclusively by immune cells subsets, mainly T cells, while its receptor is expressed on epithelial cells, such as PTCs. Functionally, IL-22 acts as a double-edged sword, with both protective and pathological functions in kidney injury. Here we elucidated the source of IL-22 in the kidney and its physiological function in nephrotoxic injury.
Patient biopsies were obtained as part of standard clinical practice. IL-22 RNA was detected by RNAScope in situ hybridization staining. IL-22 protein was detected by injecting mice with the secretion inhibitor brefeldin A and immunofluorescence staining. Nephrotoxic AKI was induced by administration of aristolochic acid (AA) or cisplatin in 8 to 12-week-old male wild-type (WT); IL-22 globally knockout mice (IL-22KO), and kidney specific IL-22 receptor knockout (Six2:IL-22RA1fl/fl, IL-22DPT). Rag1 knockout mice were used as an immune deficient model.
RNAScope staining revealed that injured PTCs were a source of IL-22 in both human and mouse AKI. Under basal conditions, no RNA or protein expression of IL-22 was observed in the kidneys. In patient biopsies and all kidney injury models, PTCs stained positive for IL-22 RNA and protein. Urinary IL-22 was 10x higher than serum levels following AKI. Immune deficient Rag1KO mice, lacking mature T and B cells, produced similar urinary IL-22 concentration compared to WT mice. Next, we analyzed the role of IL-22 in nephrotoxic kidney injury by injuring IL-22KO and IL-22DPT mice with cisplatin or AA. Both IL-22KO and IL-22DPT mice had reduced markers of DNA damage and cell death following injury, as well as increased survival and improved kidney function compared to WT.
PTCs represent the first epithelial cells found to express IL-22 and are the main contributors to urinary IL-22. Blocking IL-22 or deletion of the IL-22 receptor prevents PTC cell death and restores kidney function.