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Generation of a Primary Hyperoxaluria Type 1 Disease Model Via CRISPR/Cas9 System in Rats
- Source :
- Current Molecular Medicine. 18:436-447
- Publication Year :
- 2019
- Publisher :
- Bentham Science Publishers Ltd., 2019.
-
Abstract
- Background Primary hyperoxaluria type 1 (PH1) is an inherited disease caused by mutations in alanine-glyoxylate aminotransferase (AGXT). It is characterized by abnormal metabolism of glyoxylic acid in the liver leading to endogenous oxalate overproduction and deposition of oxalate in multiple organs, mainly the kidney. Patients of PH1 often suffer from recurrent urinary tract stones, and finally renal failure. There is no effective treatment other than combined liver-kidney transplantation. Methods Microinjection was administered to PH1 rats. Urine samples were collected for urine analysis. Kidney tissues were for Western blotting, quantitative PCR, AGT assays and histological evaluation. Results In this study, we generated a novel PH1 disease model through CRISPR/Cas9 mediated disruption of mitochondrial localized Agxt gene isoform in rats. Agxt-deficient rats excreted more oxalate in the urine than WT animals. Meanwhile, mutant rats exhibited crystalluria and showed a slight dilatation of renal tubules with mild fibrosis in the kidney. When supplied with 0.4% ethylene glycol (EG) in drinking water, mutant rats excreted greater abundance of oxalate and developed severe nephrocalcinosis in contrast to WT animals. Significantly elevated expression of inflammation- and fibrosisrelated genes was also detected in mutants. Conclusion These data suggest that Agxt-deficiency in mitochondria impairs glyoxylic acid metabolism and leads to PH1 in rats. This rat strain would not only be a useful model for the study of the pathogenesis and pathology of PH1 but also a valuable tool for the development and evaluation of innovative drugs and therapeutics.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Biochemistry
Oxalate
Pathogenesis
Primary hyperoxaluria
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Fibrosis
Internal medicine
medicine
Crystalluria
Animals
Molecular Biology
Transaminases
Oxalates
Kidney
Chemistry
Glyoxylates
General Medicine
medicine.disease
Mitochondria
Rats
Transplantation
Disease Models, Animal
Nephrocalcinosis
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Hyperoxaluria, Primary
Molecular Medicine
CRISPR-Cas Systems
Rats, Transgenic
medicine.symptom
030215 immunology
Subjects
Details
- ISSN :
- 15665240
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Current Molecular Medicine
- Accession number :
- edsair.doi.dedup.....50245e48c38df05256cfc7a92c62692b