ArticleThe Journal of clinical investigation2017
Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 64 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
- Lipocalin-2 Is Induced by Uromodulin Aggregates without Affecting Kidney Disease Progression in Autosomal Dominant Tubulointerstitial Kidney Disease- UMOD.Journal of the American Society of Nephrology : JASN · 2026Article
- Autosomal Dominant Tubulointerstitial Kidney Disease-UMOD: Case Report and Disease Update.Diagnostics (Basel, Switzerland) · 2026Article
- Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD.Nature communications · 2026Article
- Emerging Mechanistic Roles of STING Signaling in Kidney Diseases.The American journal of pathology · 2026Review
- The Influence of Sex and Hormones on Organelle Stress in Kidney Injury: Insights from Preclinical Models.Biology · 2026Review
- 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
- Endoplasmic reticulum stress in diseases.MedComm · 2024Review
- Tauroursodeoxycholic acid ameliorates renal injury induced by COL4A3 mutation.Kidney international · 2024Article
- Transport activity regulates mitochondrial bioenergetics and biogenesis in renal tubules.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Review
- 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
- High-throughput data on circular RNA reveal novel insights into chronic glomerulonephritis.Genes & genomics · 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
- Two sides of the same coin: a complex presentation of autosomal dominant tubulointerstitial kidney diseases: a literature review and case reports.Frontiers in pediatrics · 2023Article
- Autosomal Dominant Tubulointerstitial Kidney Disease: An Emerging Cause of Genetic CKD.Kidney international reports · 2022Review
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9 authors at 1 institution in 1 country.
Funding
Abstract
Uromodulin-associated kidney disease (UAKD) is caused by mutations in the uromodulin (UMOD) gene that result in a misfolded form of UMOD protein, which is normally secreted by nephrons. In UAKD patients, mutant UMOD is poorly secreted and accumulates in the ER of distal kidney epithelium, but its role in disease progression is largely unknown. Here, we modeled UMOD accumulation in mice by expressing the murine equivalent of the human UMOD p.Cys148Trp point mutation (UmodC147W/+ mice). Like affected humans, these UmodC147W/+ mice developed spontaneous and progressive kidney disease with organ failure over 24 weeks. Analysis of diseased kidneys and purified UMOD-producing cells revealed early activation of the PKR-like ER kinase/activating transcription factor 4 (PERK/ATF4) ER stress pathway, innate immune mediators, and increased apoptotic signaling, including caspase-3 activation. Unexpectedly, we also detected autophagy deficiency. Human cells expressing UMOD p.Cys147Trp recapitulated the findings in UmodC147W/+ mice, and autophagy activation with mTOR inhibitors stimulated the intracellular removal of aggregated mutant UMOD. Human cells producing mutant UMOD were susceptible to TNF-α- and TRAIL-mediated apoptosis due to increased expression of the ER stress mediator tribbles-3. Blocking TNF-α in vivo with the soluble recombinant fusion protein TNFR:Fc slowed disease progression in UmodC147W/+ mice by reducing active caspase-3, thereby preventing tubule cell death and loss of epithelial function. These findings reveal a targetable mechanism for disease processes involved in UAKD.
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