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
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
Externí odkaz: