Lithium treatment induces a marked proliferation of primarily principal cells in rat kidney inner medullary collecting duct

Am J Physiol Renal Physiol. 2006 Jul;291(1):F39-48. doi: 10.1152/ajprenal.00383.2005. Epub 2006 Jan 24.


Lithium (Li) treatment for 4 wk has previously been shown to increase the fraction of intercalated cells in parallel with a decrease in the fraction of principal cells in the kidney collecting duct (Christensen BM, Marples D, Kim YH, Wang W, Frøkiaer J, and Nielsen S. Am J Physiol Cell Physiol 286: C952-C964, 2004; Kim YH, Kwon TH, Christensen BM, Nielsen J, Wall SM, Madsen KM, Frøkiaer J, and Nielsen S. Am J Physiol Renal Physiol 285: F1244-F1257, 2003). To study how early this fractional change starts, the origin of the cells and the possible mechanism behind the changes, we did time course studies in rats subjected to different durations of Li treatment (i.e., for 4, 10, and 15 days). Increased urine output was already observed at day 4 of Li treatment with decreased AQP2 levels although not statistically significant. At days 10 and 15, both a significant polyuria and downregulation in AQP2 expression were observed. At day 10, the density of H+-ATPase-positive cells was increased in the IMCD of Li-treated rats and this was further pronounced at day 15. Some of the H+-ATPase-positive cells did not costain with Cl-/HCO3- exchanger AE1, indicating that they were not fully differentiated to type A IC. By double labeling for either H+-ATPase and proliferating-cell nuclear antigen (PCNA) or for AQP4 and PCNA, we found that proliferation mainly occurred in proximal IMCD cells at day 4 and it increased toward the middle part of the IMCD in response to prolonged Li treatment. Most cells expressing PCNA were stained with AQP4 but not with H+-ATPase. Triple-labeling for H+-ATPase, AQP4, and PCNA showed a subset of cells negative for all three proteins or only positive for PCNA. In contrast, a 4-wk recovery period after 4 wk of Li treatment reversed the enhanced proliferative rate to the control levels. In conclusion, the Li-induced increase in the density of intercalated cells is associated with a high proliferative rate of principal cells in the IM-1 and IM-2 rather than a selective proliferation of intercalated cells as expected. This is likely to contribute to the remodeling of the collecting duct after Li treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anion Exchange Protein 1, Erythrocyte / metabolism
  • Apoptosis / drug effects
  • Apoptosis Inducing Factor
  • Aquaporin 2 / metabolism
  • Aquaporin 4 / metabolism
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects*
  • Diabetes Insipidus / chemically induced
  • Diabetes Insipidus / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Immunohistochemistry
  • Kidney Medulla / chemistry
  • Kidney Medulla / cytology*
  • Kidney Medulla / drug effects*
  • Kidney Tubules, Collecting / chemistry
  • Kidney Tubules, Collecting / cytology*
  • Kidney Tubules, Collecting / drug effects*
  • Lithium / adverse effects
  • Lithium / pharmacology*
  • Male
  • Mitosis / drug effects
  • Polyuria / chemically induced
  • Proliferating Cell Nuclear Antigen / metabolism
  • Proton-Translocating ATPases / metabolism
  • Rats
  • Rats, Wistar
  • Time Factors


  • Aifm1 protein, rat
  • Anion Exchange Protein 1, Erythrocyte
  • Apoptosis Inducing Factor
  • Aqp2 protein, rat
  • Aqp4 protein, rat
  • Aquaporin 2
  • Aquaporin 4
  • Proliferating Cell Nuclear Antigen
  • Lithium
  • Proton-Translocating ATPases