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
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