Remodeling the cellular profile of collecting ducts by chronic carbonic anhydrase inhibition
Remodeling the cellular profile of collecting ducts by chronic carbonic anhydrase inhibition
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DOI：
10.1152/ajprenal.2001.280.3.f437
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发表时间：
2001-03-01
影响因子：
4.2
通讯作者：
Brown, D
中科院分区：
文献类型：
--
作者：
Bagnis, C;Marshansky, V;Brown, D
调节肾集合管中主细胞 (PC) 以及 A 和 B 嵌入细胞 (IC) 分化表型的因素知之甚少。然而，我们之前已经证明，碳酸酐酶 II (CAII) 缺陷小鼠的髓质集合管中没有 IC，这表明该酶在确定该小管段的细胞组成中具有潜在作用。我们现在报道，通过使用含有乙酰唑胺的渗透泵抑制大鼠的 CA 活性，可以重塑成年大鼠集合管的细胞特征。液泡H+-ATP酶的31-kDa亚基、钠/氢交换调节因子NHE-RF和阴离子交换器AE1用于通过免疫荧光染色鉴定IC亚型，而水通道蛋白2和水通道蛋白4用于鉴定PC。在用乙酰唑胺治疗2周的动物的皮质集合管中，B-IC的百分比显着下降（18+/-2与36+/-4%，P<0.01），而A-IC的百分比增加（82+/-2与64+/-4%，P<0.01），但上皮中总IC的百分比没有变化。在一些接受治疗的大鼠中，B-IC 几乎检测不到。在外髓质的内条纹中，治疗动物的 IC 百分比增加（48 +/- 2 vs. 37 +/- 3%，P< 0.05），而 PC 百分比下降（52 +/- 2 vs. 63 +/- 3%，P < 0.05）。此外，与对照大鼠相比，IC显得更大，突出到管腔中，并且其顶端长度（20.8 +/- 0.5 vs. 14.6 +/- 0.4 mum，P < 0.05）和基底膜长度（25.8 +/- 0.4 vs. 23.8 +/- 0.5 m，P < 0.05）显着增加。在治疗动物的内髓集合管中，乳头近三分之一处的 IC 数量与对照组相比有所减少（11 +/- 4 vs. 40 +/- 11 IC/mm(2)，P< 0.05）。这些数据表明，CA 活性在确定髓质集合管上皮细胞的分化表型中起着重要作用，并且即使在成年大鼠中，集合管的细胞特征也可以被重塑。皮质B-IC的相对消耗和髓质中A-IC的数量和增生的相对增加可能是适应性过程，其倾向于纠正或稳定代谢性酸中毒，否则代谢性酸中毒会在全身碳酸酐酶抑制后发生。
Factors regulating the differentiated phenotype of principal cells (PC) and A- and B-intercalated cells (IC) in kidney collecting ducts are poorly understood. However, we have shown previously that carbonic anhydrase II (CAII)-deficient mice have no IC in their medullary collecting ducts, suggesting a potential role for this enzyme in determining the cellular composition of this tubule segment. We now report that the cellular profile of the collecting ducts of adult rats can be remodeled by inhibiting CA activity in rats by using osmotic pumps containing acetazolamide. The 31-kDa subunit of the vacuolar H+-ATPase, the sodium/hydrogen exchanger regulatory factor NHE-RF, and the anion exchanger AE1 were used to identify IC subtypes by immunofluorescence staining, while aquaporin 2 and aquaporin 4 were used to identify PC. In the cortical collecting ducts of animals treated with acetazolamide for 2 wk, the percentage of B-IC decreased significantly (18 +/- 2 vs. 36 +/- 4%, P< 0.01) whereas the percentage of A- IC increased (82 +/- 2 vs. 64 +/- 4%, P< 0.01) with no change in the percentage of total IC in the epithelium. In some treated rats, B-IC were virtually undetectable. In the inner stripe of the outer medulla, the percentage of IC increased in treated animals (48 +/- 2 vs. 37 +/- 3%, P< 0.05) and the percentage of PC decreased (52 +/- 2 vs. 63 +/- 3%, P< 0.05). Moreover, IC appeared bulkier, protruded into the lumen, and showed a significant increase in the length of their apical (20.8 +/- 0.5 vs. 14.6 +/- 0.4 mum, P< 0.05) and basolateral membranes (25.8 +/- 0.4 vs. 23.8 +/- 0.5 m, P< 0.05) compared with control rats. In the inner medullary collecting ducts of treated animals, the number of IC in the proximal third of the papilla was reduced compared with controls (11 +/- 4 vs. 40 +/- 11 IC/mm(2), P< 0.05). These data suggest that CA activity plays an important role in determining the differentiated phenotype of medullary collecting duct epithelial cells and that the cellular profile of collecting ducts can be remodeled even in adult rats. The relative depletion of cortical B-IC and the relative increase in number and hyperplasia of A- IC in the medulla may be adaptive processes that would tend to correct or stabilize the metabolic acidosis that would otherwise ensue following systemic carbonic anhydrase inhibition.