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.