Point mutation in D8C domain of Tamm-Horsfall protein/uromodulin in transgenic mice causes progressive renal damage and hyperuricemia
Autor: | John C. Lieske, Yan Liu, Xue-Ru Wu, Nichole K. Landry, Tarek M. El-Achkar, Lijie Ma |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Tamm–Horsfall protein Physiology 030232 urology & nephrology lcsh:Medicine Apoptosis Urine Kidney Biochemistry Pathogenesis chemistry.chemical_compound Mice 0302 clinical medicine Medicine and Health Sciences Hyperuricemia lcsh:Science Staining Multidisciplinary biology Cell Death Animal Models Body Fluids Chemistry medicine.anatomical_structure Experimental Organism Systems Cell Processes Creatinine Physical Sciences Anatomy Research Article Genetically modified mouse medicine.medical_specialty Mice Transgenic Mouse Models Research and Analysis Methods 03 medical and health sciences Model Organisms Internal medicine Uromodulin medicine Animals Point Mutation Immunohistochemistry Techniques Cytoplasmic Staining business.industry urogenital system lcsh:R Chemical Compounds Biology and Life Sciences Kidneys Renal System Cell Biology medicine.disease Uric Acid Histochemistry and Cytochemistry Techniques 030104 developmental biology Endocrinology chemistry Specimen Preparation and Treatment ROMK biology.protein Cancer research Unfolded Protein Response Immunologic Techniques Uric acid lcsh:Q business Acids Biomarkers |
Zdroj: | PLoS ONE, Vol 12, Iss 11, p e0186769 (2017) PLoS ONE |
ISSN: | 1932-6203 |
Popis: | 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. |
Databáze: | OpenAIRE |
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