Fardoun Riham Zein, Asghar Mohammad, Lokhandwala Mustafa
Heart and Kidney Institute, College of Pharmacy, Univ. of Houston, Houston, TX 77204-5041, USA.
Am J Physiol Renal Physiol. 2006 Nov;291(5):F945-51. doi: 10.1152/ajprenal.00111.2006. Epub 2006 Jun 6.
Aging is associated with an increase in oxidative stress. Previously, we have reported that dopamine failed to inhibit proximal tubular Na-K-ATPase and to promote sodium excretion in old rats (Beheray S, Kansra V, Hussain T, and Lokhandwala MF. Kidney Int 58: 712-720, 2000). This was due to uncoupling of dopamine D1 receptors from G proteins resulting from hyperphosphorylation of D1 receptors. The present study was designed to test the role of oxidative stress in the age-related decline in renal dopamine D1 receptor function. We observed that old animals had increased malondialdehyde (MDA) levels, a biomarker of oxidative stress, and decreased D1 receptor number and protein in the proximal tubules (PT) compared with adult rats. In old rats, there was increased G protein-coupled receptor kinase-2 (GRK-2) abundance, increased basal serine phosphorylation of D1 receptors, and defective D1 receptor-G protein coupling in PT membranes. Interestingly, supplementation with an antioxidant, tempol (1 mmol/l in drinking water for 15 days), lowered MDA levels and normalized D1 receptor number and protein in old rats to the level seen in adult rats. Furthermore, tempol decreased GRK-2 abundance and D1 receptor serine phosphorylation and restored D1 receptor-G protein coupling in PT of old rats. The functional consequence of these changes was the restoration of the natriuretic response to D1 receptor activation in tempol-supplemented old rats. Therefore, in old rats, tempol reduces oxidative stress and prevents GRK-2 membranous abundance and hyperphosphorylation of D1 receptors, resulting in restoration of D1 receptor-G protein coupling and the natriuretic response to SKF-38393. Thus tempol, by lowering oxidative stress, normalizes the age-related decline in dopamine receptor function.
衰老与氧化应激增加相关。此前，我们报道过多巴胺无法抑制老年大鼠近端肾小管的钠钾ATP酶，也不能促进钠排泄（Beheray S、Kansra V、Hussain T和Lokhandwala MF。《肾脏国际》58：712 - 720，2000）。这是由于D1受体过度磷酸化导致多巴胺D1受体与G蛋白解偶联。本研究旨在测试氧化应激在与年龄相关的肾多巴胺D1受体功能衰退中的作用。我们观察到，与成年大鼠相比，老年动物的丙二醛（MDA）水平升高（氧化应激的生物标志物），近端肾小管（PT）中的D1受体数量和蛋白减少。在老年大鼠中，G蛋白偶联受体激酶-2（GRK - 2）丰度增加，D1受体的基础丝氨酸磷酸化增加，且PT膜中D1受体 - G蛋白偶联存在缺陷。有趣的是，补充抗氧化剂tempol（饮用水中1 mmol/l，持续15天）可降低老年大鼠的MDA水平，并使D1受体数量和蛋白恢复到成年大鼠的水平。此外，tempol降低了老年大鼠PT中的GRK - 2丰度和D1受体丝氨酸磷酸化，并恢复了D1受体 - G蛋白偶联。这些变化的功能后果是恢复了补充tempol的老年大鼠对D1受体激活的利钠反应。因此，在老年大鼠中，tempol可降低氧化应激，防止GRK - 2在膜上的丰度增加和D1受体的过度磷酸化，从而恢复D1受体 - G蛋白偶联以及对SKF - 38393的利钠反应。因此，tempol通过降低氧化应激，使与年龄相关的多巴胺受体功能衰退正常化。
