Elevated glucose in kidney organoids induces tissue-intrinsic inflammation driving epithelial detachment

2025 · doi:10.1101/2025.09.05.669416
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Elevated glucose in human kidney organoids causes tissue-intrinsic inflammation and epithelial detachment via cytokine upregulation, a phenotype targetable by therapeutic inhibitors.

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This paper studied how elevated glucose affects human kidney organoids, using organoid treatment with high glucose to model aspects of diabetic kidney disease. The authors found that high glucose causes podocyte and tubular epithelial detachment characterized by morphological deterioration without cytotoxicity, driven by tissue-intrinsic upregulation of proinflammatory cytokines; adding cytokines also sensitized organoids to intermediate glucose levels. Transcriptomic analyses showed glucose-related changes in cytokine, inflammation, signaling, and cell adhesion pathways that resemble patterns in human diabetic kidneys, and cytokine or signaling pathway inhibitors rescued the detachment phenotype, independent of osmotic effects. A major limitation is that the model is organoid-based and focuses on kidney tissue responses rather than organismal disease progression. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

ABSTRACT Diabetic kidney disease involves hyperglycemia, inflammation, and epithelial cell dysfunction, but the relationship between these factors is not well understood. We demonstrate that human kidney organoids treated with elevated glucose exhibit a phenotype of epithelial detachment driven by tissue-intrinsic upregulation of proinflammatory cytokines, which can be targeted therapeutically. High glucose induces morphological deterioration of organoids featuring podocyte and tubular cell detachment without cytotoxicity. Cytokine addition sensitizes organoids to intermediate concentrations of elevated glucose. Transcriptomic analysis reveals that high glucose levels affect cytokine, inflammation, signaling, and cell adhesion pathways, resembling changes in human diabetic kidneys. Inhibitors of cytokines and signaling pathways rescue the high glucose phenotype, which is independent of osmotic effects. Thus, elevated glucose triggers a tissue-intrinsic inflammatory cascade to produce an organ-specific phenotype in epithelial cells. This paradigm is relevant for understanding and potentially treating diabetic complications in the kidneys and possibly other organs.
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ABSTRACT Diabetic kidney disease involves hyperglycemia, inflammation, and epithelial cell dysfunction, but the relationship between these factors is not well understood. We demonstrate that human kidney organoids treated with elevated glucose exhibit a phenotype of epithelial detachment driven by tissue-intrinsic upregulation of proinflammatory cytokines, which can be targeted therapeutically. High glucose induces morphological deterioration of organoids featuring podocyte and tubular cell detachment without cytotoxicity. Cytokine addition sensitizes organoids to intermediate concentrations of elevated glucose. Transcriptomic analysis reveals that high glucose levels affect cytokine, inflammation, signaling, and cell adhesion pathways, resembling changes in human diabetic kidneys. Inhibitors of cytokines and signaling pathways rescue the high glucose phenotype, which is independent of osmotic effects. Thus, elevated glucose triggers a tissue-intrinsic inflammatory cascade to produce an organ-specific phenotype in epithelial cells. This paradigm is relevant for understanding and potentially treating diabetic complications in the kidneys and possibly other organs. Competing Interest Statement Novo Nordisk markets and develops drugs for diabetic disease, including DKD, and holds patents related to their use. AK, HHW, and VD hold shareholder interest in Novo Nordisk. BSF is an inventor on patents and/or patent applications related to human kidney organoid differentiation and disease modeling (these include Three-dimensional differentiation of epiblast spheroids into kidney tubular organoids modeling human microphysiology, toxicology, and morphogenesis [Japan, US, and Australia], licensed to STEMCELL Technologies; High-throughput automation of organoids for identifying therapeutic strategies [PTC patent application pending]; Systems and methods for characterizing pathophysiology [PTC patent application pending]. BSF holds ownership interest in Plurexa LLC.

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