Role of nuclear factor kappa B (NF-kappaB) in oxidative stress-induced defective dopamine D1 receptor signaling in the renal proximal tubules of Sprague-Dawley rats.
Role of nuclear factor kappa B (NF-kappaB) in oxidative stress-induced defective dopamine D1 receptor signaling in the renal proximal tubules of Sprague-Dawley rats.
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核因子 kappa B (NF-kappaB) 在氧化应激诱导的 Sprague-Dawley 大鼠肾近曲小管缺陷多巴胺 D1 受体信号传导中的作用。
DOI：
10.1016/j.freeradbiomed.2006.11.033
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发表时间：
2007
影响因子：
7.4
通讯作者：
Lokhandwala,Mustafa
中科院分区：
文献类型：
--
作者：
Fardoun,RihamZein;Asghar,Mohammad;Lokhandwala,Mustafa
多巴胺促进钠排泄，部分是通过激活肾近端小管（PT）中的D1受体和随后抑制Na，K-ATP酶。最近，我们报道了氧化应激通过蛋白激酶C（PKC）和G蛋白偶联受体激酶2（GRK 2）引起SD大鼠肾PT原代培养物中D1受体-G蛋白解偶联。有报道表明，氧化还原敏感性核转录因子NF-κB在与氧化应激相关的条件下被激活。本研究旨在确定NF-κB在氧化应激诱导的肾D1受体-G蛋白偶联和功能缺陷中的作用。用过氧化氢（H2 O2，50 μM/20 min）处理PT可诱导NF-κB核转位，增加PKC活性，并触发GRK 2转位至近端小管膜。这是伴随着D1受体和缺陷的D1受体-G蛋白偶联的过度磷酸化。这些变化的功能后果是减少D1受体激活介导的抑制Na，K-ATP酶活性。有趣的是，用NF-κB抑制剂吡咯烷二硫代氨基甲酸酯（PDTC，25 μM/10 min）预处理可阻断H2 O2诱导的NF-κB核转位、PKC活性增加、GRK 2转位和近端肾小管膜D1受体过度磷酸化。此外，PDTC恢复了D1受体G蛋白偶联和D1受体激动剂介导的对Na，K-ATP酶活性的抑制。因此，我们认为，氧化应激导致NF-κB在肾近端小管的核转位，这有助于缺陷的D1受体-G-蛋白偶联和功能，通过涉及PKC，GRK 2的膜转位，以及随后的多巴胺D1受体磷酸化的机制。
Dopamine promotes sodium excretion, in part, via activation of D1 receptors in renal proximal tubules (PT) and subsequent inhibition of Na, K-ATPase. Recently, we have reported that oxidative stress causes D1 receptor–G-protein uncoupling via mechanisms involving protein kinase C (PKC) and G-protein-coupled receptor kinase 2 (GRK 2) in the primary cultures of renal PT of Sprague-Dawley (SD) rats. There are reports suggesting that redox-sensitive nuclear transcription factor, NF-κB, is activated in conditions associated with oxidative stress. This study was designed to identify the role of NF-κB in oxidative stress-induced defective renal D1 receptor–G-protein coupling and function. Treatment of the PT with hydrogen peroxide (H2O2, 50 μM/20 min) induced the nuclear translocation of NF-κB, increased PKC activity, and triggered the translocation of GRK 2 to the proximal tubular membranes. This was accompanied by hyperphosphorylation of D1 receptors and defective D1 receptor–G-protein coupling. The functional consequence of these changes was decreased D1 receptor activation-mediated inhibition of Na, K-ATPase activity. Interestingly, pretreatment with pyrrolidine dithiocarbamate (PDTC, 25 μM/10 min), an NF-κB inhibitor, blocked the H2O2-induced nuclear translocation of NF-κB, increase in PKC activity, and GRK 2 translocation and hyperphosphorylation of D1 receptors in the proximal tubular membranes. Furthermore, PDTC restored D1 receptor G-protein coupling and D1 receptor agonist-mediated inhibition of the Na, K-ATPase activity. Therefore, we suggest that oxidative stress causes nuclear translocation of NF-κB in the renal proximal tubules, which contributes to defective D1 receptor–G-protein coupling and function via mechanisms involving PKC, membranous translocation of GRK 2, and subsequent phosphorylation of dopamine D1 receptors.