Aqp2⁺ Progenitor Cells Maintain and Repair Distal Renal Segments

Background Adult progenitor cells presumably demonstrate clonogenicity, self-renewal, and multipotentiality, and can regenerate cells under various conditions. Definitive evidence demonstrating the existence of such progenitor cells in adult mammalian kidneys is lacking.

Method We performed in vivo lineage tracing and thymidine analogue labeling using adult tamoxifen-inducible (Aqp2^ECE/+ RFP/+, Aqp2^ECE/+ Brainbow/+, and Aqp2^ECE/+ Brainbow/Brainbow) and WT mice. The tamoxifen-inducible mice were analyzed between 1 and 300 days postinduction. Alternatively, WT and tamoxifen-induced mice were subjected to unilateral ureteral obstruction and thymidine analogue labeling and analyzed 2–14 days post-surgery. Multiple cell-specific markers were used for high-resolution immunofluorescence confocal microscopy to identify the cell types derived from Aqp2⁺ cells.

Results Like their embryonic counterparts, adult cells expressing Aqp2 and V-ATPase subunits B1 and B2 (Aqp2⁺ B1B2⁺) are the potential Aqp2⁺ progenitor cells (APs). Adult APs rarely divide to generate daughter cells, either maintaining the property of the AP (self-renewal) or differentiating into DCT2/CNT/CD cells (multipotentiality), forming single cell–derived, multiple-cell clones (clonogenicity) during tissue maintenance. APs selectively and continuously regenerate DCT2/CNT/CD cells in response to injury resulting from ureteral ligation. AP proliferation demonstrated direct correlation with Notch activation and was inversely correlated with development of kidney fibrosis. Derivation of both intercalated and DCT2 cells was found to be cell division–dependent and –independent, most likely through AP differentiation which requires cell division and through direct conversion of APs and/or regular principal cells without cell division, respectively.

Conclusion Our study demonstrates that Aqp2⁺ B1B2⁺ cells behave as adult APs to maintain and repair DCT2/CNT1/CNT2/CD segments.