ArticlePloS one2017
Mutant uromodulin expression leads to altered homeostasis of the endoplasmic reticulum and activates the unfolded protein response.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 50 citations in OpenAlex.
- A novel and two recurrent UMOD mutations in autosomal dominant tubulointerstitial kidney disease (ADTKD): a case series and literature review.Renal failure · 2026Review
- Calorie Restriction Leads to Degradation of Mutant Uromodulin and Ameliorates Inflammation and Fibrosis in UMOD -Related Kidney Disease.Journal of the American Society of Nephrology : JASN · 2026Article
- Recent advances in the clinical significance and physiological functions of uromodulin: a narrative review.BMC nephrology · 2026Review
- Mutations in UMOD Contribute to the Pathogenesis of ADTKD-UMOD by Influencing the Function of Complement Factor H.Journal of cellular and molecular medicine · 2026Article
- Review
- Early renal response to long-term salt loading: mitochondrial dysfunction, ER stress, and uromodulin accumulation in the kidney medulla.American journal of physiology. Renal physiology · 2025Article
- Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease.Nature reviews. Nephrology · 2025Review
- Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors.The Journal of clinical investigation · 2024Article
- Advances in uromodulin biology and potential clinical applications.Nature reviews. Nephrology · 2024Review
- Anatomical and molecular insights into the antennal gland of the giant freshwater prawn Macrobrachium rosenbergii.Cell and tissue research · 2024Article
- The Versatile Role of Uromodulin in Renal Homeostasis and Its Relevance in Chronic Kidney Disease.Internal medicine (Tokyo, Japan) · 2024Review
- Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease.EMBO molecular medicine · 2023Article
- MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice.Nature communications · 2023Article
- A founderJournal of medical genetics · 2023Article
- Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2023Article
- Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside.Frontiers in cell and developmental biology · 2023Review
- Autosomal Dominant Tubulointerstitial Kidney Disease: An Emerging Cause of Genetic CKD.Kidney international reports · 2022Review
- Article
- Article
- An intermediate-effect size variant inProceedings of the National Academy of Sciences of the United States of America · 2022Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Uromodulin is the most abundant urinary protein in physiological conditions. It is exclusively produced by renal epithelial cells lining the thick ascending limb of Henle's loop (TAL) and it plays key roles in kidney function and disease. Mutations in UMOD, the gene encoding uromodulin, cause autosomal dominant tubulointerstitial kidney disease uromodulin-related (ADTKD-UMOD), characterised by hyperuricemia, gout and progressive loss of renal function. While the primary effect of UMOD mutations, retention in the endoplasmic reticulum (ER), is well established, its downstream effects are still largely unknown. To gain insight into ADTKD-UMOD pathogenesis, we performed transcriptional profiling and biochemical characterisation of cellular models (immortalised mouse TAL cells) of robust expression of wild type or mutant GFP-tagged uromodulin. In this model mutant uromodulin accumulation in the ER does not impact on cell viability and proliferation. Transcriptional profiling identified 109 genes that are differentially expressed in mutant cells relative to wild type ones. Up-regulated genes include several ER resident chaperones and protein disulphide isomerases. Consistently, pathway enrichment analysis indicates that mutant uromodulin expression affects ER function and protein homeostasis. Interestingly, mutant uromodulin expression induces the Unfolded Protein Response (UPR), and specifically the IRE1 branch, as shown by an increased splicing of XBP1. Consistent with UPR induction, we show increased interaction of mutant uromodulin with ER chaperones Bip, calnexin and PDI. Using metabolic labelling, we also demonstrate that while autophagy plays no role, mutant protein is partially degraded by the proteasome through ER-associated degradation. Our work demonstrates that ER stress could play a central role in ADTKD-UMOD pathogenesis. This sets the bases for future work to develop novel therapeutic strategies through modulation of ER homeostasis and associated protein degradation pathways.
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