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

Hereditary tyrosinemia type 1 (HT1) (McKusick 276700), a severe autosomal r ecessive disorder of tyrosine metabolism, is caused by mutations in the fum arylacetoacetate hydrolase gene Fah (EC 3.7.1.2), which encodes the last en zyme in the tyrosine catabolic pathway. HT1 is characterized by severe prog ressive liver disease and renal tubular dysfunction. Homozygous disruption of the gene encoding Fah in mice causes neonatal lethality (e.g., lethal Al bino deletion c(14CoS) mice), an event that limits use of this animal as a model for HT1. A new mouse model was developed with two genetic defects, Fa h and 4-hydroxyphenylpyruvate dioxygenase (Hpd). The Fah(-/-)Hpd(-/-) mice grew normally without evidence of liver and renal disease, and the phenotyp e is similar to that in Fah(+/+)Hpd(-/-) mice. The renal tubular cells of F ah(-/-)Hpd(-/-) mice, particularly proximal tubular cells, underwent rapid apoptosis when homogentisate, the intermediate metabolite between HPD and F AH, was administered to the Fah(-/-)Hpd(-/-) mice. Simultaneously, renal tu bular function was impaired and Fanconi syndrome occurred. Apoptotic death of renal tubular cells, but not renal dysfunction, was prevented by pretrea tment of the animals with YVAD, a specific inhibitor of caspases. In the ho mogentisate-treated Fah(-/-)Hpd(-/-) mice, massive amounts of succinylaceto ne were excreted into the urine, regardless of treatment with inhibitors. I t is suggested that apoptotic death of renal tubular cells, as induced by a dministration of homogentisate to Fah(-/-)Hpd(-/-) mice, was caused by an i ntrinsic process, and that renal apoptosis and tubular dysfunctions in tubu lar cells occurred through different pathways. These observations shed ligh t on the pathogenesis of renal tubular injury in subjects with FAH deficien cy. These Fah(-/-)Hpd(-/-) mice can serve as a model in experiments related to renal tubular damage.