ArticlePloS one2017
Point mutation in D8C domain of Tamm-Horsfall protein/uromodulin in transgenic mice causes progressive renal damage and hyperuricemia.
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 7 papers.
What it found
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Who cites it
7 citing papers in PubMed, 19 citations in OpenAlex.
- Advances in uromodulin biology and potential clinical applications.Nature reviews. Nephrology · 2024Review
- Uromodulin biology.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2024Review
- The presence of xanthine dehydrogenase is crucial for the maturation of the rat kidneys.Clinical science (London, England : 1979) · 2024Article
- The Versatile Role of Uromodulin in Renal Homeostasis and Its Relevance in Chronic Kidney Disease.Internal medicine (Tokyo, Japan) · 2024Review
- 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
- Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein.Scientific reports · 2019Article
- Mouse models for human hyperuricaemia: a critical review.Nature reviews. Rheumatology · 2019Review
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance. Both the young and the old transgenic mice had significantly higher serum uric acid and its catabolic product, allantoin, than age-matched wild-type mice. This THP mutation apparently caused primary defects in TAL by compromising the luminal translocation and reabsorptive functions of NKCC2 and ROMK and secondary responses in proximal tubules by upregulating NHE3 and URAT1. Our results strongly suggest that the progressive worsening of kidney functions reflects the accumulation of the deleterious effects of the misfolded mutant THP and the compensatory responses. Transgenic mice recapitulating human THP/uromodulin-associated kidney diseases could be used to elucidate their pathogenesis and test novel therapeutic strategies.
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Registered trials
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