Evaluation of cellular plasticity in the collecting duct during recovery from lithium-induced nephrogenic diabetes insipidus

Am J Physiol Renal Physiol. 2013 Sep 15;305(6):F919-29. doi: 10.1152/ajprenal.00152.2012. Epub 2013 Jul 3.


The cellular morphology of the collecting duct is altered by chronic lithium treatment. We have previously shown that lithium increases the fraction of type-A intercalated cells and lowers the fraction of principal cells along the collecting duct. Moreover, type-A intercalated cells acquire a long-row distribution pattern along the tubules. In the present study, we show that these morphological changes reverse progressively after discontinuation of lithium and finally disappear after 19 days from lithium suspension. In this time frame we have identified for the first time, in vivo, a novel cellular type positive for both intercalated and principal cells functional markers, as recognized by colabeling with H(+)-ATPase/aquaporin-4 (AQP4) and anion exchanger-1 (AE-1)/AQP2 and Foxi1/AQP4. This cell type is mainly present after 6 days of lithium washout, and it disappears in parallel with the long-row pattern of the type-A intercalated cells. It usually localizes either in the middle or at the edge of the long-row pattern. Its ultrastructure resembles the intercalated cells as shown both by differential interference contrast and by electron microscopy. The time course of appearance, the localization along the collecting duct, and the ultrastructure suggest that the cells double labeled for principal and intercalated cells markers could represent a transition element driving the conversion of intercalated cells into principal cells.

Keywords: AQP2; H+-ATPase; cellular plasticity; intercalated cell; principal cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 2 / biosynthesis
  • Aquaporin 4 / biosynthesis
  • Cell Proliferation
  • Diabetes Insipidus, Nephrogenic / chemically induced*
  • Diabetes Insipidus, Nephrogenic / metabolism
  • Diabetes Insipidus, Nephrogenic / pathology*
  • Forkhead Transcription Factors / biosynthesis
  • Kidney Tubules, Collecting / cytology*
  • Lithium / adverse effects*
  • Male
  • Proton-Translocating ATPases / biosynthesis
  • Rats
  • Substance Withdrawal Syndrome* / pathology


  • Aqp2 protein, rat
  • Aqp4 protein, rat
  • Aquaporin 2
  • Aquaporin 4
  • Forkhead Transcription Factors
  • Lithium
  • Proton-Translocating ATPases