Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1

Marjanka C. Luijerink, Ellen A C M Van Beurden, Helga E M Malingré, Saskia M M Jacobs, Markus Grompe, Leo W J Klomp, Ruud Berger, Inge E T Van Den Berg

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 Kidneys of adult Fah-/- mice, withdrawn from NTBC for 15 days, reveal limited characteristics of apoptosis, and have acquired resistance to a caspase-9- and caspase-3-independent form of cell death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.

Original languageEnglish (US)
Pages (from-to)990-1000
Number of pages11
JournalKidney International
Volume66
Issue number3
DOIs
StatePublished - Sep 2004
Externally publishedYes

Fingerprint

Tyrosinemias
Homogentisic Acid
Cell Death
Kidney
Caspase 3
Caspase 9
Tyrosine
Apoptosis
Deoxyuridine
DNA Nucleotidylexotransferase
Diphosphates
Liver Failure
In Situ Nick-End Labeling
DNA Fragmentation
Enzymes
1,3-cyclohexanedione
Knockout Mice
Renal Insufficiency
Phenotype

Keywords

  • Acquired resistance to cell death
  • Apoptotic cell death
  • Caspase-3
  • Caspase-9
  • Hereditary tyrosinemia type 1
  • Kidney damage

ASJC Scopus subject areas

  • Nephrology

Cite this

Luijerink, M. C., Van Beurden, E. A. C. M., Malingré, H. E. M., Jacobs, S. M. M., Grompe, M., Klomp, L. W. J., ... Van Den Berg, I. E. T. (2004). Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1. Kidney International, 66(3), 990-1000. https://doi.org/10.1111/j.1523-1755.2004.00788.x

Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1. / Luijerink, Marjanka C.; Van Beurden, Ellen A C M; Malingré, Helga E M; Jacobs, Saskia M M; Grompe, Markus; Klomp, Leo W J; Berger, Ruud; Van Den Berg, Inge E T.

In: Kidney International, Vol. 66, No. 3, 09.2004, p. 990-1000.

Research output: Contribution to journalArticle

Luijerink, MC, Van Beurden, EACM, Malingré, HEM, Jacobs, SMM, Grompe, M, Klomp, LWJ, Berger, R & Van Den Berg, IET 2004, 'Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1', Kidney International, vol. 66, no. 3, pp. 990-1000. https://doi.org/10.1111/j.1523-1755.2004.00788.x
Luijerink, Marjanka C. ; Van Beurden, Ellen A C M ; Malingré, Helga E M ; Jacobs, Saskia M M ; Grompe, Markus ; Klomp, Leo W J ; Berger, Ruud ; Van Den Berg, Inge E T. / Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1. In: Kidney International. 2004 ; Vol. 66, No. 3. pp. 990-1000.
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abstract = "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.",
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AU - Jacobs, Saskia M M

AU - Grompe, Markus

AU - Klomp, Leo W J

AU - Berger, Ruud

AU - Van Den Berg, Inge E T

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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.

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KW - Hereditary tyrosinemia type 1

KW - Kidney damage

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