title: A mouse model of renal tubular injury of tyrosinemia type 1: development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice.
abstract: Hereditary tyrosinemia type 1 (HT1) (McKusick 276700), a severe autosomal recessive disorder of tyrosine metabolism, is caused by mutations in the fumarylacetoacetate hydrolase gene Fah (EC 3.7.1.2), which encodes the last enzyme in the tyrosine catabolic pathway. HT1 is characterized by severe progressive liver disease and renal tubular dysfunction. Homozygous disruption of the gene encoding Fah in mice causes neonatal lethality (e.g., lethal Albino deletion c14CoS mice), an event that limits use of this animal as a model for HT1. A new mouse model was developed with two genetic defects, Fah and 4-hydroxyphenylpyruvate dioxygenase (Hpd). The Fah-/- Hpd-/- mice grew normally without evidence of liver and renal disease, and the phenotype is similar to that in Fah+/+ Hpd-/- mice. The renal tubular cells of Fah-/- Hpd-/- mice, particularly proximal tubular cells, underwent rapid apoptosis when homogentisate, the intermediate metabolite between HPD and FAH, was administered to the Fah-/- Hpd-/- mice. Simultaneously, renal tubular function was impaired and Fanconi syndrome occurred. Apoptotic death of renal tubular cells, but not renal dysfunction, was prevented by pretreatment of the animals with YVAD, a specific inhibitor of caspases. In the homogentisate-treated Fah-/- Hpd-/- mice, massive amounts of succinylacetone were excreted into the urine, regardless of treatment with inhibitors. It is suggested that apoptotic death of renal tubular cells, as induced by administration of homogentisate to Fah-/- Hpd-/- mice, was caused by an intrinsic process, and that renal apoptosis and tubular dysfunctions in tubular cells occurred through different pathways. These observations shed light on the pathogenesis of renal tubular injury in subjects with FAH deficiency. These Fah-/- Hpd-/- mice can serve as a model in experiments related to renal tubular damage.
authors.affiliation: Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Mao-Sen
authors.initials: MS
authors.lastname: Sun
authors.affiliation: The College of Medical Sciences, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Shinzaburo
authors.initials: S
authors.lastname: Hattori
authors.affiliation: Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kubo
authors.affiliation: Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Awata
authors.affiliation: Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Matsuda
authors.affiliation: Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Endo
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005198:Fanconi Syndrome / Q000150:complications; D006867:Hydrolases / Q000235:genetics; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D020176:Tyrosinemias / Q000150:complications / Q000378:metabolism / Q000473:pathology*
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C096429:L 709049; D015111:4-Hydroxyphenylpyruvate Dioxygenase; D006867:Hydrolases; C020156:fumarylacetoacetase