Early targets of lithium in rat kidney inner medullary collecting duct include p38 and ERK1/2

Kidney Int. 2014 Oct;86(4):757-67. doi: 10.1038/ki.2014.107. Epub 2014 Apr 30.


Almost half of patients receiving lithium salts have nephrogenic diabetes insipidus. Chronic lithium exposure induces AQP2 downregulation and changes in the cellular composition of the collecting duct. In order to understand these pathophysiological events, we determined the earliest lithium targets in rat inner medullary collecting duct (IMCD) by examining changes in the IMCD phosphoproteome after acute lithium administration. IMCDs were isolated 9 h after lithium exposure, a time when urinary concentrating impairment was evident. We found 1093 unique phosphopeptides corresponding to 492 phosphoproteins identified and quantified by mass spectrometry. Label-free quantification identified 152 upregulated and 56 downregulated phosphopeptides in response to lithium. Bioinformatic analysis highlighted several signaling proteins including MAP kinases and cell-junction proteins. The majority of the upregulated phosphopeptides contained a proline-directed motif, a known target of MAPK. Four hours after lithium exposure, phosphorylation sites in the activation loops of ERK1/2 and p38 were upregulated. Increased expression of phospho-Ser261-AQP2 (proline-directed motif) was concomitant with the increase in urine output. Pretreatment with MAPK inhibitors reversed the increased Ser261-AQP2 phosphorylation. Thus, in IMCD, ERK1/2 and p38 are early targets of lithium and may play a role in the onset of lithium-induced polyuria.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Insipidus, Nephrogenic / chemically induced
  • Down-Regulation / drug effects
  • Kidney Tubules, Collecting / drug effects
  • Kidney Tubules, Collecting / enzymology
  • Kidney Tubules, Collecting / metabolism*
  • Lithium Compounds / adverse effects
  • Lithium Compounds / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mass Spectrometry
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Interaction Domains and Motifs
  • Protein Kinase Inhibitors / pharmacology
  • Proteome / metabolism*
  • Rats
  • Rats, Wistar
  • Up-Regulation / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Lithium Compounds
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Proteome
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases