Renal β-intercalated cells maintain body fluid and electrolyte balance
Renal β-intercalated cells maintain body fluid and electrolyte balance
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DOI：
10.1172/jci63492
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发表时间：
2013-10-01
影响因子：
15.9
通讯作者：
Chambrey, Regine
中科院分区：
文献类型：
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作者：
Gueutin, Victor;Vallet, Marion;Chambrey, Regine
插层细胞（ic）中B1质子泵亚基（ATP6V1B1）失活导致I型远端肾小管酸中毒（dRTA），这是一种与盐和钾丢失肾病相关的疾病。本研究表明，缺乏ATP6V1B1的小鼠（ATP6V1B1（-/-）小鼠）表现出肾脏NaCl、K+和水的损失，导致低血容量、低钾血症和多尿。研究结果表明，NaCl损失源于皮质收集管，上皮钠通道（ENaC）和pendin /Na+驱动的氯化物/碳酸氢盐交换器（pendin /NDCBE）运输系统的活性均受到损害。ENaC在髓质集管中适当增加，提示皮质中存在局部抑制。我们在Atp6v1b1（-/-）小鼠中检测到高水平的尿前列腺素E-2 （PGE(2)）和ATP。体内抑制PGE(2)合成可恢复ENaC蛋白水平，特别是在皮质中。它还使大电导钙活化钾通道和水通道水通道蛋白2的蛋白水平正常化，并改善突变小鼠的多尿和低钾血症。此外，β - ic中质子泵的药理失活通过激活钙偶联嘌呤能受体诱导PGE的释放(2)。在本研究中，我们发现atp触发的源自β - ic的PGE(2)旁分泌信号是与d.RTA相关的水电解质失衡发展的机制。我们的数据表明，除了主细胞外，ic在维持钠平衡，从而维持正常的血管容量和血压方面也至关重要。
Inactivation of the B1 proton pump subunit (ATP6V1B1) in intercalated cells (ICs) leads to type I distal renal tubular acidosis (dRTA), a disease associated with salt- and potassium-losing nephropathy. Here we show that mice deficient in ATP6V1B1 (Atp6v1b1(-/-) mice) displayed renal loss of NaCl, K+, and water, causing hypovolemia, hypokalemia, and polyuria. We demonstrated that NaCl loss originated from the cortical collecting duct, where activity of both the epithelial sodium channel (ENaC) and the pendrin/Na+-driven chloride/bicarbonate exchanger (pendrin/NDCBE) transport system was impaired. ENaC was appropriately increased in the medullary collecting duct, suggesting a localized inhibition in the cortex. We detected high urinary prostaglandin E-2 (PGE(2)) and ATP levels in Atp6v1b1(-/-) mice. Inhibition of PGE(2) synthesis in vivo restored ENaC protein levels specifically in the cortex. It also normalized protein levels of the large conductance calcium-activated potassium channel and the water channel aquaporin 2, and improved polyuria and hypokalemia in mutant mice. Furthermore, pharmacological inactivation of the proton pump in beta-ICs induced release of PGE(2) through activation of calcium-coupled purinergic receptors. In the present study, we identified ATP-triggered PGE(2) paracrine signaling originating from beta-ICs as a mechanism in the development of the hydroelectrolytic imbalance associated with d.RTA. Our data indicate that in addition to principal cells, ICs are also critical in maintaining sodium balance and, hence, normal vascular volume and blood pressure.