EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2-Mediated Renal Water Reabsorption.
Nephrogenic diabetes insipidus (NDI) is caused by impairment of vasopressin (VP) receptor type 2 signaling. Because potential therapies for NDI that target the canonical VP/cAMP/protein kinase A pathway have so far proven ineffective, alternative strategies for modulating aquaporin 2 (AQP2) trafficking have been sought. Successful identification of compounds by our high-throughput chemical screening assay prompted us to determine whether EGF receptor (EGFR) inhibitors stimulate AQP2 trafficking and reduce urine output. Erlotinib, a selective EGFR inhibitor, enhanced AQP2 apical membrane expression in collecting duct principal cells and reduced urine volume by 45% after 5 days of treatment in mice with lithium-induced NDI. Similar to VP, erlotinib increased exocytosis and decreased endocytosis in LLC-PK1 cells, resulting in a significant increase in AQP2 membrane accumulation. Erlotinib increased phosphorylation of AQP2 at Ser-256 and Ser-269 and decreased phosphorylation at Ser-261 in a dose-dependent manner. However, unlike VP, the effect of erlotinib was independent of cAMP, cGMP, and protein kinase A. Conversely, EGF reduced VP-induced AQP2 Ser-256 phosphorylation, suggesting crosstalk between VP and EGF in AQP2 trafficking and a role of EGF in water homeostasis. These results reveal a novel pathway that contributes to the regulation of AQP2-mediated water reabsorption and suggest new potential therapeutic strategies for NDI treatment.
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Pui W
PW
Cheung
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Naohiro
N
Nomura
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Anil V
AV
Nair
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Nutthapoom
N
Pathomthongtaweechai
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Lars
L
Ueberdiek
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Hua A Jenny
HA
Lu
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Dennis
D
Brown
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts Bouley.Richard@mgh.harvard.edu.
Richard
R
Bouley
D000818:Animals; D051399:Aquaporin 2 / Q000187:drug effects* / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D014867:Water / Q000378:metabolism*
D051399:Aquaporin 2; D014867:Water; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
Cell Signaling; diabetes insipidus; water channels
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