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首页> 外文期刊>American Journal of Physiology >α-Ketoglutarate stimulates pendrin-dependent Cl? absorption in the mouse CCD through protein kinase C
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α-Ketoglutarate stimulates pendrin-dependent Cl? absorption in the mouse CCD through protein kinase C

机译：α-酮抑制刺激pendrin依赖的cl？ 通过蛋白激酶C在小鼠CCD中吸收

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摘要

α-Ketoglutarate (α-KG) is a citric acid cycle intermediate and a glutamine catabolism product. It is also the natural ligand of 2-oxoglutarate receptor 1 (OXGR1), a Gq protein-coupled receptor expressed on the apical membrane of intercalated cells. In the cortical collecting duct (CCD), Cl?/HCO3? exchange increases upon α-KG binding to the OXGR1. To determine the signaling pathway(s) by which α-KG stimulates Cl? absorption, we examined α-KG-stimulated Cl? absorption in isolated perfused mouse CCDs. α-KG increased electroneutral Cl? absorption in CCDs from wild-type mice but had no effect on Cl? absorption in pendrin knockout mice. Because Gq protein-coupled receptors activate PKC, we hypothesized that α-KG stimulates Cl? absorption through PKC. If so, PKC agonists should mimic, whereas PKC inhibitors should abolish, α-KG-stimulated Cl? absorption. Like α-KG, PKC agonist (phorbol-12,13-dibutyrate, 500 nM) application increased Cl? absorption in wild-type but not in pendrin null CCDs. Moreover, PKC inhibitors (2.5 mM GF109203X and 20 nM calphostin C), Ca2+ chelators (BAPTA, 10–20 μM), or PKC-α or -δ gene ablation eliminated α-KG-stimulated Cl? absorption. We have shown that STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) gene ablation increases urinary α-KG excretion, renal pendrin abundance, and CCD Cl? absorption. However, in SPAK null CCDs, Cl? absorption was not activated further by luminal α-KG application nor was Cl? absorption reduced with the PKC inhibitor GF109203. Thus SPAK gene ablation likely acts through a PKC-independent pathway to produce a chronic adaptive increase in pendrin function. In conclusion, α-KG stimulates pendrin-dependent Cl?/HCO3? exchange through a mechanism dependent on PKC and Ca2+ that involves PKC-α and PKC-δ.
机译：α-酮戊酸盐（α-Kg）是柠檬酸循环中间体和谷​​氨酰胺分解代谢产物。它也是2-氧缺乏酸酯受体1（OXGR1）的天然配体，在插层细胞的顶端膜上表达的GQ蛋白偶联受体。在皮质收集管道（CCD）中，CL？/ HCO3？交换增加α-kg与Oxg1的结合。确定α-kg刺激Cl的信令路径？吸收，我们检查了α-kg刺激的cl？在分离的灌注小鼠CCD中吸收。 α-kg增加电阻Cl？来自野生型小鼠的CCD中的吸收，但对CL没有影响？ Pendrin敲除小鼠中的吸收。因为GQ蛋白偶联受体激活PKC，所以我们假设α-kg刺激CL？通过PKC吸收。如果是这样，PKC激动剂应该模仿，而PKC抑制剂应该废除，α-KG刺激的CL？吸收。与α-kg，pkc激动剂（Phorbol-12,13-二丁酸盐，500nm）施用增加了Cl？野生型吸收但不在Pendrin Null CCD中。此外，PKC抑制剂（2.5mM GF109203x和20nm Calphostin c），Ca2 +螯合剂（Bapta，10-20μm）或pKc-α或-Δ基因消融消除了α-kg刺激的Cl？吸收。我们已经表明，STE20 / SPS-1相关的脯氨酸 - 富含丙氨酸 - 富含丙氨酸 - 基因消融增加了尿α-Kg排泄，肾病素丰度和CCD CL？吸收。但是，在spak null ccds，cl？腔α-kg申请还没有进一步激活吸收，也不是Cl？用PKC抑制剂GF109203减少吸收。因此，Spak基因消融可能通过与PKC无关的途径作用，以产生pendrin功能的慢性自适应增加。总之，α-kg刺激pendrin依赖的cl？/ hco3？通过依赖于PKC和CA2 +的机制交换，所述PKC-α和PKC-δ。

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