Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1
Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1
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DOI：
10.1172/jci200420665
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发表时间：
2004-06-01
影响因子：
15.9
通讯作者：
Enerbäck, S
中科院分区：
文献类型：
--
作者：
Blomqvist, SR;Vidarsson, H;Enerbäck, S
虽然缺乏Foxi1的小鼠的宏观和微观肾脏发育似乎正常进行，但电子显微镜显示远端肾单位衬里的细胞的超微结构发生了变化。Northern印迹分析、cRNA原位杂交和免疫组织化学显示，集合管间质细胞表达的几种阴离子转运蛋白、质子泵和阴离子交换蛋白完全缺失，其中许多与遗传性远端肾小管酸中毒(DRTA)有关。在Foxi1缺失突变体中，正常上皮及其两种主要细胞类型--主细胞和间质细胞--已经被一种主细胞和间质细胞标记均阳性的单细胞类型所取代。为了测试这些改变的功能后果，Foxi1(-/-)小鼠与WT产仔鼠在酸性负荷下的反应进行了比较。这揭示了尿液酸化的能力，以及系统缓冲能力的降低和零突变的明显酸中毒。因此，Foxi1(-/-)小鼠似乎由于远端肾单位上皮细胞成分的改变而发生DRTA，从而使该上皮细胞无法获得维持足够的酸碱平衡所需的适当基因表达模式。
While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types - principal and intercalated cells - has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1(-/-) mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1(-/-) mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.