Schwartz George J, Gao XiaoBo, Tsuruoka Shuichi, Purkerson Jeffrey M, Peng Hu, D'Agati Vivette, Picard Nicolas, Eladari Dominique, Al-Awqati Qais
J Clin Invest. 2015 Oct 26;125(12):4365-74. doi: 10.1172/JCI80225.
The nephron cortical collecting duct (CCD) is composed of principal cells, which mediate Na, K, and water transport, and intercalated cells (ICs), which are specialized for acid-base transport. There are two canonical IC forms: acid-secreting α-ICs and HCO3-secreting β-ICs. Chronic acidosis increases α-ICs at the expense of β-ICs, thereby increasing net acid secretion by the CCD. We found by growth factor quantitative PCR array that acidosis increases expression of mRNA encoding SDF1 (or CXCL12) in kidney cortex and isolated CCDs from mouse and rabbit kidney cortex. Exogenous SDF1 or pH 6.8 media increased H+ secretion and decreased HCO3 secretion in isolated perfused rabbit CCDs. Acid-dependent changes in H+ and HCO3 secretion were largely blunted by AMD3100, which selectively blocks the SDF1 receptor CXCR4. In mice, diet-induced chronic acidosis increased α-ICs and decreased β-ICs. Additionally, IC-specific Cxcr4 deletion prevented IC subtype alterations and magnified metabolic acidosis. SDF1 was transcriptionally regulated and a target of the hypoxia-sensing transcription factor HIF1α. IC-specific deletion of Hif1a produced no effect on mice fed an acid diet, as α-ICs increased and β-ICs decreased similarly to that observed in WT littermates. However, Hif1a deletion in all CCD cells prevented acidosis-induced IC subtype distribution, resulting in more severe acidosis. Cultured principal cells exhibited an HIF1α-dependent increase of Sdf1 transcription in response to media acidification. Thus, our results indicate that principal cells respond to acid by producing SDF1, which then acts on adjacent ICs.
肾单位皮质集合管（CCD）由介导钠、钾和水转运的主细胞以及专门负责酸碱转运的闰细胞（ICs）组成。有两种典型的闰细胞形式：分泌酸的α-闰细胞和分泌HCO3的β-闰细胞。慢性酸中毒会以β-闰细胞为代价增加α-闰细胞，从而增加CCD的净酸分泌。我们通过生长因子定量PCR阵列发现，酸中毒会增加小鼠和兔肾皮质肾皮质中编码SDF1（或CXCL12）的mRNA表达，并从肾皮质中分离出CCD。外源性SDF1或pH 6.8的培养基会增加分离的灌注兔CCD中的H+分泌并减少HCO3分泌。AMD3100可选择性阻断SDF1受体CXCR4，从而在很大程度上减弱了H+和HCO3分泌的酸依赖性变化。在小鼠中，饮食诱导的慢性酸中毒会增加α-闰细胞并减少β-闰细胞。此外，IC特异性Cxcr4缺失可防止IC亚型改变并加重代谢性酸中毒。SDF1受到转录调控，是缺氧感应转录因子HIF1α的靶标。IC特异性缺失Hif1a对喂食酸性饮食的小鼠没有影响，因为α-闰细胞增加而β-闰细胞减少，这与野生型同窝小鼠中观察到的情况相似。然而，所有CCD细胞中的Hif1a缺失可防止酸中毒诱导性IC亚型分布，从而导致更严重的酸中毒。培养的主细胞在响应培养基酸化时表现出HIF1α依赖性的Sdf1转录增加。因此，我们的结果表明，主细胞通过产生SDF1对酸作出反应，然后SDF1作用于相邻的闰细胞。
