TY - JOUR
T1 - Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1
AU - Luijerink, Marjanka C.
AU - Van Beurden, Ellen A.C.M.
AU - Malingré, Helga E.M.
AU - Jacobs, Saskia M.M.
AU - Grompe, Markus
AU - Klomp, Leo W.J.
AU - Berger, Ruud
AU - Van Den Berg, Inge E.T.
N1 - Funding Information:
We gratefully thank Dr. R. Goldschmeding for evaluation and description of kidney damage, and Helma Straver for measurement of succinylacetone levels. NTBC was kindly supplied by Swedish Orphan AB, Stockholm, Sweden. This work was supported by grant SW04 from the STER-project, Wilhelmina Children's Hospital Foundation.
PY - 2004/9
Y1 - 2004/9
N2 - 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-l- 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-l- 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-l- 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. Conclusion. Kidneys of adult Fah-/- mice, withdrawn from NTBC for 15 days, reveal limited characteristics of apoptosis, and have acquired resistance to a caspase-9- and caspase-3-independent form of cell death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.
AB - 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-l- 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-l- 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-l- 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. Conclusion. 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.
KW - Acquired resistance to cell death
KW - Apoptotic cell death
KW - Caspase-3
KW - Caspase-9
KW - Hereditary tyrosinemia type 1
KW - Kidney damage
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U2 - 10.1111/j.1523-1755.2004.00788.x
DO - 10.1111/j.1523-1755.2004.00788.x
M3 - Article
C2 - 15327392
AN - SCOPUS:4344611693
SN - 0085-2538
VL - 66
SP - 990
EP - 1000
JO - Kidney International
JF - Kidney International
IS - 3
ER -