Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa
Autor: | Erica L. Fletcher, Monica L. Acosta, Yea-Seul Shin, David L. Christie, Sarah Ready, Michael Kalloniatis |
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Rok vydání: | 2010 |
Předmět: |
Phosphocreatine
genetic structures Phosphodiesterase Inhibitors Physiology ATPase Apoptosis Piperazines Rats Sprague-Dawley chemistry.chemical_compound Adenosine Triphosphate Sulfones Creatine Kinase biology Age Factors medicine.anatomical_structure Disease Progression Rats Transgenic Sodium-Potassium-Exchanging ATPase Retinitis Pigmentosa Monocarboxylic Acid Transporters medicine.medical_specialty Programmed cell death Coumaric Acids Proline Retina Sildenafil Citrate Internal medicine Retinitis pigmentosa medicine Animals Sensory Rhodopsins Histidine L-Lactate Dehydrogenase Membrane Transport Proteins Retinal Cell Biology Creatine medicine.disease eye diseases Rats Disease Models Animal Endocrinology chemistry Purines Mutation biology.protein Creatine kinase Ca(2+) Mg(2+)-ATPase sense organs Energy Metabolism |
Zdroj: | American Journal of Physiology-Cell Physiology. 298:C764-C774 |
ISSN: | 1522-1563 0363-6143 |
Popis: | We determined the metabolic changes that precede cell death in the dystrophic proline-23-histidine (P23H) line 3 (P23H-3) rat retina compared with the normal Sprague-Dawley (SD) rat retina. Metabolite levels and metabolic enzymes were analyzed early in development and during the early stages of degeneration in the P23H-3 retina. Control and degenerating retinas showed an age-dependent change in metabolite levels and enzymatic activity, particularly around the time when phototransduction was activated. However, lactate dehydrogenase (LDH) activity was significantly higher in P23H-3 than SD retina before the onset of photoreceptor death. The creatine/phosphocreatine system did not contribute to the increase in ATP, because phosphocreatine levels, creatine kinase, and expression of the creatine transporter remained constant. However, Na+-K+-ATPase and Mg2+-Ca2+-ATPase activities were increased in the developing P23H-3 retina. Therefore, photoreceptor apoptosis in the P23H-3 retina occurs in an environment of increased LDH, ATPase activity, and higher-than-normal ATP levels. We tested the effect of metabolic challenge to the retina by inhibiting monocarboxylate transport with α-cyano-4-hydroxycinnamic acid or systemically administering the phosphodiesterase inhibitor sildenafil. Secondary to monocarboxylate transport inhibition, the P23H-3 retina did not demonstrate alterations in metabolic activity. However, administration of sildenafil significantly reduced LDH activity in the P23H-3 retina and increased the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end-labeled photoreceptor cells. Photoreceptor cells with a rhodopsin mutation display an increase in apoptotic markers secondary to inhibition of a phototransduction enzyme (phosphodiesterase), suggesting increased susceptibility to altered cation entry. |
Databáze: | OpenAIRE |
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