Podocyte Interleukin‐23 Receptor Signaling in the Pathogenesis of Lupus Nephritis

Objective Up-regulation of interleukin-23 (IL-23) in the serum and kidneys of patients with lupus nephritis (LN) has been demonstrated, but its effect on podocytes remains unknown. We hypothesized that IL-23 contributes to podocyte injury and that targeted deletion of IL-23 receptor (IL-23R) in podocytes of lupus-prone mice can prevent the development of glomerulonephritis.

Kidney biopsies were immunostained for IL-23R. In vitro experiments were conducted using a human podocyte cell line and primary murine podocytes. Human podocytes stimulated with IL-23 underwent bulk RNA sequencing. The expression of IL-23R and structure and motility of podocytes were assessed. Podocytes isolated from B6 wild-type mice injected with a minicircle (MC) encoding IL-23 were studied. To assess the role of IL-23R in the development of nephritis, we generated MRL/lpr mice deficient in podocyte-specific Il23r who were lupus prone.

IL-23R was highly expressed in the glomeruli of patients with LN. IL-23R expression was also up-regulated in human podocytes and primary podocytes isolated from B6 mice after IL-23 stimulation. Human podocytes stimulated with IL-23 showed decreased expression of synaptopodin and remodeling of the actin cytoskeleton. Mice who were administered with IL-23 MC mice exhibited a significant increase in the expression of IL-23R and phosphorylated STAT3 in podocytes. Finally, MRL/lpr.Podo-Cre+ Il23rfl/fl mice showed decreased clinical and histologic features of LN.

IL-23R expression is increased in podocytes from mice and humans with systemic lupus erythematosus. IL-23 signaling disrupts the cytoskeleton in podocytes and increases their mobility, leading to the development of glomerulonephritis. Podocyte-specific deletion of Il23r in lupus-prone mice abrogates the development of LN. Supporting Information | Filename | Description | |---|---| | art43395-sup-0001-Disclosureform.pdfPDF document, 671.3 KB | Disclosure form. | | art43395-sup-0002-TableS1.docxWord 2007 document , 15.9 KB | Supplementary Table 1: Characteristics of patients with lupus nephritis at the time of kidney biopsy | Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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