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GPR91 deletion improves lithium‐induced nephrogenic diabetes insipidus
Author(s) -
Lam Lisa,
Gevorgyan Haykanush A,
Riquier-Brison Anne DM,
Peti-Peterdi Janos
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.1100.5
Subject(s) - polyuria , nephrogenic diabetes insipidus , medicine , endocrinology , aquaporin 2 , diabetes insipidus , lithium (medication) , urine osmolality , excretion , chemistry , diabetes mellitus , water channel , mechanical engineering , engineering , inlet
Lithium (Li) is a commonly used treatment for bipolar disorders. However, the use of Li is complicated by its renal side effect causing nephrogenic diabetes insipidus (NDI). The mechanism by which Li causes NDI is incompletely understood but cyclooxygenase 2 (COX‐2) and prostaglandin E2 (PGE2) are primary players. It has been established that Li inhibits luminal uptake of dicarboxylates including succinate resulting in their increased urinary excretion. Succinate is the ligand of the newly discovered metabolic receptor GPR91 that is highly expressed in the collecting ducts and its signaling involves COX‐2 and PGE2. Therefore, we tested the hypothesis that GPR91 plays an important role in Li‐induced NDI. Wild type (WT) and GPR91 −/− mice (n=5 each) were fed normal and Li‐added diets for 14 days and then euthanized to collect kidney tissues. Li‐induced polyuria was significantly less in GPR91 −/− mice (osmolality=604.85 ± 56.96 mOsm, urine output=10.96 ± 1.07 ml/24h) compared to WT mice (osmolality=394.60 ± 29.81 mOsm, urine output=19.37 ± 1.30 ml/24h) with no significant difference in Li intake. AQP2 protein abundance in the medulla was 1.5 fold higher in Li‐treated GPR91 −/− versus WT mice. Also, urinary succinate excretion progressively increased during Li treatment. These data suggest that deletion of GPR91 leads to a significant resistance to Li‐induced polyuria and may provide a novel therapeutic strategy.