Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa.
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 Mg(2+)-Ca(2+)-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 alpha-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.
Acosta
Monica L
ML
Department of Optometry and Vision Science, University of Auckland, Auckland, New Zealand.
Shin
Yea-Seul
YS
Ready
Sarah
S
Fletcher
Erica L
EL
Christie
David L
DL
Kalloniatis
Michael
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D003373:Coumaric Acids / Q000494:pharmacology; D003401:Creatine / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism / Q000187:drug effects; D006639:Histidine; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D010725:Phosphocreatine / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011392:Proline; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025603:Sensory Rhodopsins / Q000235:genetics*; D000068677:Sildenafil Citrate; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology
D003373:Coumaric Acids; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D025603:Sensory Rhodopsins; D013450:Sulfones; C080679:creatine transporter; D010725:Phosphocreatine; C007175:alpha-cyano-4-hydroxycinnamate; D006639:Histidine; D000255:Adenosine Triphosphate; D011392:Proline; D000068677:Sildenafil Citrate; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D003401:Creatine