IL-32 Is a Lipid Droplet-Associated Mediator of Tubular Injury in Diabetic Kidney Disease
Bibliographic record
Abstract
Background: Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. The mechanisms contributing to DKD progression remains poorly characterized. In biopsies of human DKD, lipid droplets (LD) accumulate primarily in tubules with advanced stages of DKD. The contribution of lipid dysregulation is not well understood for DKD. Here we use human kidney biopsies and DKD patient-derived kidney organoids to investigate how LDs contribute to the pathogenesis of DKD. Methods: Human kidney biopsies of the DKD as classified by the Renal Pathology Society classification of DKD were stained using Nile Red and analyzed to LD distribution and numbers. To model DKD, induced pluripotent stem cells (iPSC) were reprogrammed from healthy controls and DKD patients and differentiated to kidney organoids. Kidney organoids were treated with diabetic conditions in the absence of the SGLT2 inhibitor canagliflozin and analyzed by single cell RNA sequencing, in vitro assays, digital spatial imaging (CosMx), molecular spatial imaging (GeoMx) and live kidney organoid imaging. Results: High glucose uptake promoted prominent LD formation in proximal tubular cells (PTC) of human kidney organoids derived from the iPSC of DKD patients. Single cell RNA sequencing of kidney organoids identified IL32, a gene encoding a pro-inflammatory cytokine induced by high glucose and downregulated by the SGLT2 inhibitor canagliflozin. Analysis of human DKD biopsies by Nanostring's digital spatial transcriptomics and molecular spatial imaging confirmed enrichment of IL32 mRNA in injured proximal tubules. In human DKD organoids, IL-32 localized to tubular LD and its upregulation led to mitochondrial reactive oxygen species generation, mitochondrial fragmentation and tubular basement membrane thickening, attenuated by IL32 knockdown. Overexpression of the beta and gamma isoforms of IL-32 in primary human proximal tubular epithelial cells induced mitochondrial fragmentation, ROS, and caspase-3 and GSDME-mediated cell death. Conclusion: These findings identify IL-32 as a potential mediator linking metabolic dysfunction to chronic inflammation in DKD. IL-32 is a potentially targetable LD-associated cytokine that can be used to delay the progression of DKD. Funding: Government Support – Non-U.S.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".