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首页> 外文期刊>American Journal of Physiology >Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa.
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Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa.

机译：色素性视网膜炎的脯氨酸23组氨酸大鼠模型的视网膜代谢状态。

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摘要

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.
机译：与正常的Sprague-Dawley（SD）大鼠视网膜相比，我们确定了营养不良的脯氨酸23-组氨酸（P23H）3（P23H-3）大鼠视网膜中细胞死亡之前的代谢变化。在P23H-3视网膜发育的早期和变性的早期，分析了代谢物的水平和代谢酶。对照和退化的视网膜显示出代谢物水平和酶活性的年龄依赖性变化，尤其是在激活光转导前后。然而，在感光器死亡之前，P23H-3中的乳酸脱氢酶（LDH）活性显着高于SD视网膜。肌酸/磷酸肌酸系统无助于ATP的增加，因为磷酸肌酸水平，肌酸激酶和肌酸转运蛋白的表达保持恒定。但是，Na（+）-K（+）-ATPase和Mg（2 +）-Ca（2 +）-ATPase活性在发育中的P23H-3视网膜中增加。因此，P23H-3视网膜中的感光细胞凋亡发生在LDH，ATPase活性增加以及ATP水平高于正常水平的环境中。我们通过用α-氰基-4-羟基肉桂酸抑制单羧酸盐运输或系统性地施用磷酸二酯酶抑制剂西地那非来测试对视网膜的代谢挑战的影响。继单羧酸盐运输抑制后，P23H-3视网膜未显示出代谢活性的改变。但是，西地那非的给药显着降低了P23H-3视网膜中的LDH活性，并增加了末端脱氧核苷酸转移酶生物素-dUPT缺口末端标记的感光细胞的数量。具有视紫红质突变的感光细胞显示出继抑制光转导酶（磷酸二酯酶）之后凋亡标记的增加，表明对改变的阳离子进入的敏感性增加。

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