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Lithium and glycogen synthase kinase‐3 inhibition induces lysosomal degradation of aquaporin‐2
Author(s) -
Edemir Bayram,
Jardzejewski Marc,
Schlatter Eberhard
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.885.14
Subject(s) - aquaporin 2 , mg132 , gsk 3 , glycogen synthase , chemistry , western blot , microbiology and biotechnology , gsk3b , biology , kinase , glycogen , apoptosis , biochemistry , proteasome inhibitor , water channel , gene , mechanical engineering , engineering , inlet
Lithium (Li), used as treatment of bipolar disorders can lead to diabetes insipidus which shows decreased expression of aquaporin‐ 2 (AQP2) and polyuria. Li also reduces glycogen synthase kinase‐3 (GSK3) activity. GSK3beta deficient mice show decreased urinary concentration ability. The underlying cellular and molecular mechanisms are not fully understood. We used primary cultured inner medullary collecting duct (IMCD) cells, treated with Li or the GSK3 inhibitor SB216763. IMCD cells endogenously express AQP2 and other principal cell markers. AQP2 expression was verified by western blot analysis and realtime PCR. Treatment for 24h with Li or SB216763 reduced expression by 75%. Realtime PCR showed that Li treatment reduced AQP2 expression while SB216763 had no effect. The proteasom inhibitor MG132 or the lysosomal inhibitor bafilomycin (BF) reduced AQP2 mRNA but not protein expression. Li plus MG132 still reduced AQP2 expression. Li plus BF showed normal AQP2 expression. Furthermore in BF but not in MG132 treated cells AQP2 accumulated in vesicular structures. In conclusion we show that Li and GSK3 inhibition reduced AQP2 protein but only Li also mRNA expression. The accumulation of AQP2 after BF treatment indicates recycling of AQP2 in lysosoms. Li and GSK3 inhibition affect this lysosomal recycling thereby promoting lysosomal degradation of AQP2.