Furosemide-induced urinary acidification is caused by pronounced H+ secretion in the thick ascending limb
Furosemide-induced urinary acidification is caused by pronounced H+ secretion in the thick ascending limb
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DOI：
10.1152/ajprenal.00154.2015
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发表时间：
2015-07-15
影响因子：
4.2
通讯作者：
Leipziger, Jens
中科院分区：
文献类型：
--
作者：
de Bruijn, Pauline I. A.;Larsen, Casper K.;Leipziger, Jens
袢利尿剂呋塞米可抑制粗升支（TAL）的NaCl重吸收。此外，呋塞米使尿液酸化，这在传统上被解释为通过增加远端小管的Na+负载，导致通过α-插入细胞中的H+-ATP酶激活H+分泌。速尿无法酸化尿液可用于诊断远端肾小管酸中毒（α-插入细胞功能障碍）。由于TAL对酸/碱调节很重要，我们推测它参与了呋塞米诱导的尿酸化。腔呋塞米（100 μ M）引起主要的，稳定的，可逆的细胞内碱化（7.27 +/- 0.06至7.6 +/- 0.04）在隔离灌注的小鼠骨髓TAL和明显的H+分泌。用鲁米那阿米洛利（1 mM）和Na+/H+交换剂（NHE）3特异性拮抗剂#4167（1 μ M）完全抑制H+分泌。此外，速尿触发了髓TAL细胞内Na+浓度的大幅下降。这些结果表明，呋塞米诱导的H+分泌是细胞内Na+浓度下降的结果，增加了NHE 3的驱动力。有趣的是，在整个动物实验中，特异性NHE 3抑制作用显着减少了速尿诱导的尿液酸化和净酸排泄。此外，呋塞米诱导的尿酸化部分保存在上皮Na+通道抑制与苯扎明。这些结果为呋塞米诱导的尿酸化机制提供了新的见解，并强调了TAL在肾脏酸/碱处理中的作用。
The loop diuretic furosemide inhibits NaCl reabsorption in the thick ascending limb (TAL). In addition, furosemide acidifies the urine, which is traditionally explained by increased Na+ loading to the distal tubule causing an activation of H+ secretion via H+-ATPase in alpha-intercalated cells. The inability to acidify urine in response to furosemide serves to diagnose distal renal tubular acidosis (dysfunction of alpha-intercalated cells). Since the TAL is important for acid/ base regulation, we speculated that it is involved in furosemide-induced urinary acidification. Luminal furosemide (100 mu M) caused major, stable, and reversible intracellular alkalization (7.27 +/- 0.06 to 7.6 +/- 0.04) in isolated perfused murine medullary TAL and pronounced H+ secretion. This H+ secretion was fully inhibited with luminal amiloride (1 mM) and the Na+/H+ exchanger (NHE)3-specific antagonist #4167 (1 mu M). Moreover, furosemide triggered a substantial drop of intracellular Na+ concentration in the medullary TAL. These results suggest that the furosemide-induced H+ secretion is a consequence of a drop in intracellular Na+ concentration, increasing the driving force for NHE3. Intriguingly, in whole animal experiments, furosemide-induced urinary acidification and net acid excretion were markedly reduced by specific NHE3 inhibition. Furthermore, the furosemide-induced urinary acidification was partially preserved during epithelial Na+ channel inhibition with benzamil. These results provide new insights in the mechanism of furosemide-induced urinary acidification and emphasize the role of the TAL in renal acid/base handling.