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Renal Collecting Duct Specific GSK 3 alpha Regulates Cellular Distribution and Lithium‐Induced NDI
Author(s) -
Rao Reena,
Nilsson Line,
Tao Shixin,
Woodgett James,
Norregaard Rikke
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.885.16
Subject(s) - aquaporin 2 , nephrogenic diabetes insipidus , polyuria , endocrinology , gsk 3 , medicine , chemistry , intercalated cell , immunostaining , gsk3b , kidney , microbiology and biotechnology , biology , phosphorylation , biochemistry , diabetes mellitus , water channel , mechanical engineering , immunohistochemistry , engineering , inlet
Lithium (Li) induced nephrogenic diabetes insipidus is associated with reduced Aquaporin 2 (AQP2) levels and increased proliferation of collecting duct cells (CD) in rodent models. Li is a potent inhibitor of glycogen synthase kinase 3 (GSK3). GSK3 inhibition is known to increase cell proliferation in non‐renal cells. In the current study we examined isoform specific roles of GSK3α and GSK3β in CD structure and function in normal and Li treated mice. We found that gene deletion of GSK3 alpha (3 alpha −/−) caused urinary concentrating defect and polyuria at basal conditions. In these mice, AQP2 protein levels were lower and H‐ATPase, a marker for type A intercalated cells were significantly higher, compared to WT or 3β‐CDnull mice. LiCl treatment (4mmol/Kg, daily IP injection) for 6 days increased urine output and reduced AQP2 levels in WT, but not in 3 alpha −/− mice. Immunostaining for PCNA, marker for dividing cells, AQP4 for principal cells and H‐ATPase demonstrated increase in proliferation of principal cells of cortical and medullary CD cells in WT and 3beta‐CDnull mice, but not in 3 alpha −/− mice. These studies showed that gene deletion of GSK3 alpha changed normal cell distribution in renal CD, reduced AQP2 expression and caused polyuria and that, GSK3 alpha, rather than GSK3beta, is a critical target of Li in renal CDs.