Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1
| Autor: | Helga E.M. Malingré, Ellen A.C.M. Van Beurden, L.E.O.W.J. Klomp, Ruud Berger, Inge E.T. van den Berg, Saskia M.M. Jacobs, Markus Grompe, Marjanka C. Luijerink |
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| Rok vydání: | 2004 |
| Předmět: |
caspase-3
medicine.medical_specialty Programmed cell death apoptotic cell death Hydrolases DNA Fragmentation caspase-9 Kidney Tubules Proximal Tyrosinemia Mice chemistry.chemical_compound Internal medicine In Situ Nick-End Labeling medicine Animals Homogentisic acid Enzyme Inhibitors Homogentisic Acid Caspase Mice Knockout Kidney hereditary tyrosinemia type 1 TUNEL assay biology Caspase 3 Cyclohexanones Tyrosinemias medicine.disease kidney damage Caspase 9 Survival Rate Disease Models Animal Endocrinology medicine.anatomical_structure chemistry Nephrology Apoptosis Caspases Nitrobenzoates Hepatocytes biology.protein Tyrosine Fumarylacetoacetate hydrolase acquired resistance to cell death |
| Zdroj: | Kidney International. 66:990-1000 |
| ISSN: | 0085-2538 |
| DOI: | 10.1111/j.1523-1755.2004.00788.x |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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