Point mutation in D8C domain of Tamm-Horsfall protein/uromodulin in transgenic mice causes progressive renal damage and hyperuricemia

Lijie Ma, Yan Liu, Nichole K. Landry, Tarek M. El-Achkar, John C Lieske, Xue Ru Wu

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0186769
JournalPLoS One
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2017

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hyperuricemia
Uromodulin
Hyperuricemia
point mutation
Point Mutation
Transgenic Mice
kidneys
genetically modified organisms
Kidney
Defects
mice
Allantoin
proteins
Mutation
Uric Acid
Extremities
Cysteine
Urine
Creatinine
Oliguria

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Point mutation in D8C domain of Tamm-Horsfall protein/uromodulin in transgenic mice causes progressive renal damage and hyperuricemia. / Ma, Lijie; Liu, Yan; Landry, Nichole K.; El-Achkar, Tarek M.; Lieske, John C; Wu, Xue Ru.

In: PLoS One, Vol. 12, No. 11, e0186769, 01.11.2017.

Research output: Contribution to journalArticle

Ma, Lijie ; Liu, Yan ; Landry, Nichole K. ; El-Achkar, Tarek M. ; Lieske, John C ; Wu, Xue Ru. / Point mutation in D8C domain of Tamm-Horsfall protein/uromodulin in transgenic mice causes progressive renal damage and hyperuricemia. In: PLoS One. 2017 ; Vol. 12, No. 11.
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