Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
J Am Soc Nephrol. 2013 Feb;24(2):243-52. doi: 10.1681/ASN.2012080866. Epub 2013 Jan 10.
The mammalian collecting duct comprises principal and intercalated cells, which maintain sodium/water and acid/base balance, respectively, but the epigenetic contributors to the differentiation of these cell types remain unknown. Here, we investigated whether the histone H3 K79 methyltransferase Dot1l, which is highly expressed in principal cells, participates in this process. Taking advantage of the distribution of aquaporin 2 (Aqp2), which localizes to principal cells of the collecting duct, we developed mice lacking Dot1l in Aqp2-expressing cells (Dot1l(AC)) and found that these mice had approximately 20% fewer principal cells and 13%-16% more intercalated cells than control mice. This deletion of Dot1l in principal cells abolished histone H3 K79 methylation in these cells, but unexpectedly, most intercalated cells also had undetectable di-methyl K79, suggesting that Aqp2(+) cells give rise to intercalated cells. These Aqp2(+) cell-derived intercalated cells were present in both developing and mature kidneys. Furthermore, compared with control mice, Dot1l(AC) mice had 40% higher urine volume and 18% lower urine osmolarity with relatively normal electrolyte and acid-base homeostasis. In conclusion, these data suggest that Dot1l deletion facilitates the differentiation of some α- and β-intercalated cells from Aqp2-expressing progenitor cells or mature principal cells.
哺乳动物的集合管包括主细胞和闰细胞，它们分别维持钠/水和酸碱平衡，但这些细胞类型分化的表观遗传贡献因素尚不清楚。在这里，我们研究了高度表达于主细胞中的组蛋白 H3 K79 甲基转移酶 Dot1l 是否参与这一过程。利用水通道蛋白 2（Aqp2）的分布情况，其定位于集合管的主细胞中，我们开发了在 Aqp2 表达细胞中缺乏 Dot1l 的小鼠（Dot1l(AC)），并发现这些小鼠的主细胞数量减少了约 20%，闰细胞数量增加了 13%-16%。主细胞中 Dot1l 的缺失消除了这些细胞中的组蛋白 H3 K79 甲基化，但出乎意料的是，大多数闰细胞也几乎检测不到二甲基化 K79，这表明 Aqp2(+)细胞分化为闰细胞。这些 Aqp2(+)细胞衍生的闰细胞存在于发育和成熟的肾脏中。此外，与对照组小鼠相比，Dot1l(AC)小鼠的尿液量增加了 40%，尿液渗透压降低了 18%，而电解质和酸碱平衡相对正常。总之，这些数据表明，Dot1l 的缺失促进了一些α-和β-闰细胞从 Aqp2 表达的祖细胞或成熟的主细胞分化而来。
