Effect of renal lipid accumulation on proximal tubule Na+/H+ exchange and ammonium secretion
Effect of renal lipid accumulation on proximal tubule Na+/H+ exchange and ammonium secretion
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DOI：
10.1152/ajprenal.00550.2007
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发表时间：
2008-06-01
影响因子：
4.2
通讯作者：
Moe, Orson W.
中科院分区：
文献类型：
--
作者：
Bobulescu, I. Alexandru;Dubree, Michele;Moe, Orson W.
代谢综合征患者由于尿液pH值降低和氨排泄受损，尿酸肾结石的风险增加。这些泌尿系统变化的病理生理机制尚不清楚。我们使用两种动物模型和一种细胞培养模型来研究肾脏酸化的改变是否与肾脏脂肪浸润（脂肪变性）相关。与配对喂养的瘦对照大鼠相比，Zucker糖尿病肥胖大鼠肾脏甘油三酯含量较高，尿铵和pH值降低，刷状缘膜Na+/H+交换器-3（NHE 3）水平较低，NHE 3是铵排泄的主要介质。Sprague-Dawley大鼠的高脂喂养导致尿铵和pH值的短暂降低，当动物恢复正常饮食时，所有参数均恢复正常。这与这些动物中不存在饮食诱导的肾脏脂肪变性一致。为了检查脂肪积累的直接影响，我们孵育负鼠肾（OKP）细胞与长链脂肪酸的混合物，并发现细胞内脂质的积累伴随着NHE 3活性，表面生物素可接近的NHE 3蛋白和铵分泌的剂量依赖性降低。导致细胞内脂质蓄积但不改变基线NHE 3的较低剂量的脂肪酸足以消除胰岛素对NHE 3的刺激，并部分阻断糖皮质激素对NHE 3的刺激;载脂OKP细胞中NHE 3的酸调节不受影响。这些结果表明，肾脂肪变性减少铵分泌近端小管，部分通过减少NHE 3活性和通过削弱特定激动剂的NHE 3的调节。
Patients with metabolic syndrome have increased risk of uric acid nephrolithiasis due to lower urinary pH and impaired ammonium excretion. The pathophysiology underlying these urinary changes is unknown. We used two animal models and a cell culture model to study whether the alteration in renal acidification is associated with renal fat infiltration ( steatosis). Compared with pair-fed lean control rats, Zucker diabetic fatty rats have higher renal triglyceride content, decreased urinary ammonium and pH, and lower levels of brush border membrane Na+/H+ exchanger-3 (NHE3), a major mediator of ammonium excretion. High-fat feeding in Sprague-Dawley rats results in transient lowering of urinary ammonium and pH, with all parameters returning to normal when the animals resumed eating normal chow. This is consistent with an absence of diet-induced renal steatosis in these animals. To examine the direct effect of fat accumulation, we incubated opossum kidney (OKP) cells with a mixture of long-chain fatty acids and found accumulation of intracellular lipids with concomitant dose-dependent decrease in NHE3 activity, surface biotin-accessible NHE3 protein, and ammonium secretion. A lower dose of fatty acids that leads to intracellular lipid accumulation but does not change baseline NHE3 is sufficient to abolish the stimulation of NHE3 by insulin and to partially block the stimulation of NHE3 by glucocorticoid hormones; acid regulation of NHE3 in lipid-loaded OKP cells is not affected. These findings suggest that renal steatosis decreases ammonium secretion in the proximal tubule, in part by reducing NHE3 activity and by impairing the regulation of NHE3 by specific agonists.