Aqp2-Expressing Cells Give Rise to Renal Intercalated Cells

Abstract

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 + cellderived 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 a-and b-intercalated cells from Aqp2-expressing progenitor cells or mature principal cells.

Adam10 Mediates the Choice between Principal Cells and Intercalated Cells in the Kidney

“…Recent findings in mice with a deficiency for a histone methyltransferase suggest the presence of a group of Aqp2 + "plastic PCs" that can differentiate into both PCs and ICs. 28 In the Adam10 mutants, we have observed a small population of cells that are positive for both Aqp2 and Foxi1 ( Figure 5). It is still unclear whether this population is, or overlaps with, the group of Aqp2 + "plastic PCs".…”

In situ histone landscape of nephrogenesis

“…28 The function of Dot1l in the developing kidney is unknown but it has been suggested that Dot1l-H3K79 methylation plays a role in terminal differentiation of the collecting duct. 48 Histone methylation occurs on lysine and arginine residues. Asymmetrically dimethylated H3R2me2a, catalyzed by Prmt6, lies adjacent to the active mark H3K4me3.…”

Lithium Causes G2 Arrest of Renal Principal Cells

“…Another explanation may be that these intercalated cells are derived from principal cells, because principal cells can transit to intercalated cells. 35 Perhaps the pHistone-H3-positive intercalated cells were originally principal cells, but transformed into intercalated cells upon lithium entry. In line with this hypothesis, a small subset of ISOM collecting duct cells (2.5%) expressed marker proteins of intercalated and principal cells at day 10 of lithium treatment.…”