Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1.
BACKGROUND
Hereditary tyrosinemia type 1 (HT1), which is associated with severe liver and kidney damage, is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine breakdown cascade. HT1-associated liver and kidney failure can be prevented by blocking an enzyme upstream of FAH in the tyrosine breakdown pathway with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). FAH knockout mice develop the HT1 phenotype when NTBC treatment is discontinued.


METHODS
The occurrence of cell death was investigated in kidneys of Fah(-/-) mice on and off NTBC either unchallenged or injected with 800 mg/kg of homogentisic acid (HGA), an intermediate of tyrosine breakdown.


RESULTS
No cell death could be detected in kidneys of Fah(-/-) mice on NTBC. A slight increase of cleaved caspase-3 was the only apoptosis-related feature that could be detected in kidneys of Fah(-/-) mice off NTBC. Challenge of Fah(-/-) mice on NTBC with HGA led to massive death of renal proximal tubular cells, with positive terminal deoxynucleotidyl transferase-mediated deoxyuridine diphosphate (dUDP) nick-end labeling (TUNEL) and DNA fragmentation assays, but hardly any cleavage of caspase-9 and caspase-3. Fah(-/-) mice off NTBC acquired resistance to HGA-induced renal cell death and the kidneys exhibited relatively few features of apoptosis upon challenge with HGA, with a small increase in expression of cleaved caspase-9 and caspase-3.


CONCLUSIONS
Kidneys of adult Fah(-/-) mice, withdrawn from NTBC for 15 days, reveal limited characteristics of apoptosis, and have acquired resistance to a caspase-9- and caspase-3-independent form of cell death provoked by HGA.
Department of Metabolic Diseases, University Medical Center, Utrecht, The Netherlands.
Marjanka C
MC
Luijerink
Ellen A C M
EA
van Beurden
Helga E M
HE
Malingré
Saskia M M
SM
Jacobs
Markus
M
Grompe
Leo W J
LW
Klomp
Ruud
R
Berger
Inge E T
IE
van den Berg
D000818:Animals; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003512:Cyclohexanones / Q000494:pharmacology; D053938:DNA Fragmentation / Q000502:physiology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000637:transplantation; D006713:Homogentisic Acid / Q000494:pharmacology; D006867:Hydrolases / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009579:Nitrobenzoates / Q000494:pharmacology; D015996:Survival Rate; D014443:Tyrosine / Q000378:metabolism; D020176:Tyrosinemias / Q000235:genetics / Q000401:mortality / Q000473:pathology*
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D014443:Tyrosine; D006867:Hydrolases; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; C020156:fumarylacetoacetase; C077073:nitisinone; D006713:Homogentisic Acid