Universität zu Köln

de Groot, Theun, Ebert, Lena K., Christensen, Birgitte Monster ORCID: 0000-0002-6140-4629, Andralojc, Karolina, Cheval, Lydie, Doucet, Alain, Mao, Cungui, Baumgarten, Ruben, Low, Benjamin E., Sandhoff, Roger, Wiles, Michael, V, Deen, Peter M. T. and Korstanje, Ron (2019). Identification of Acer2 as a First Susceptibility Gene for Lithium-Induced Nephrogenic Diabetes Insipidus in Mice. J. Am. Soc. Nephrol., 30 (12). S. 2322 - 2337. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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Abstract

Background Lithium, mainstay treatment for bipolar disorder, causes nephrogenic diabetes insipidus and hypercalcemia in about 20% and 10% of patients, respectively, and may lead to acidosis. These adverse effects develop in only a subset of patients treated with lithium, suggesting genetic factors play a role. Methods To identify susceptibility genes for lithium-induced adverse effects, we performed a genome-wide association study in mice, which develop such effects faster than humans. On day 8 and 10 after assigning female mice from 29 different inbred strains to normal chow or lithium diet (40 mmol/kg), we housed the animals for 48 hours in metabolic cages for urine collection. We also collected blood samples. Results In 17 strains, lithium treatment significantly elevated urine production, whereas the other 12 strains were not affected. Increased urine production strongly correlated with lower urine osmolality and elevated water intake. Lithium caused acidosis only in one mouse strain, whereas hypercalcemia was found in four strains. Lithium effects on blood pH or ionized calcium did not correlate with effects on urine production. Using genome-wide association analyses, we identified eight gene-containing loci, including a locus containing Acer2, which encodes a ceramidase and is specifically expressed in the collecting duct. Knockout of Acer2 led to increased susceptibility for lithium-induced diabetes insipidus development. Conclusions We demonstrate that genome-wide association studies in mice can be used successfully to identify susceptibility genes for development of lithium-induced adverse effects. We identified Acer2 as a first susceptibility gene for lithium-induced diabetes insipidus in mice.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code de Groot, Theun UNSPECIFIED UNSPECIFIED UNSPECIFIED Ebert, Lena K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Christensen, Birgitte Monster UNSPECIFIED orcid.org/0000-0002-6140-4629 UNSPECIFIED Andralojc, Karolina UNSPECIFIED UNSPECIFIED UNSPECIFIED Cheval, Lydie UNSPECIFIED UNSPECIFIED UNSPECIFIED Doucet, Alain UNSPECIFIED UNSPECIFIED UNSPECIFIED Mao, Cungui UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumgarten, Ruben UNSPECIFIED UNSPECIFIED UNSPECIFIED Low, Benjamin E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sandhoff, Roger UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiles, Michael, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Deen, Peter M. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Korstanje, Ron UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-125299
DOI:	10.1681/ASN.2018050549
Journal or Publication Title:	J. Am. Soc. Nephrol.
Volume:	30
Number:	12
Page Range:	S. 2322 - 2337
Date:	2019
Publisher:	AMER SOC NEPHROLOGY
Place of Publication:	WASHINGTON
ISSN:	1533-3450
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language KIDNEY COLLECTING DUCT; CELLS; RATS; AQUAPORIN-2; EXPRESSION; URINE; WATER; HYPERPARATHYROIDISM; PROLIFERATION; SPHINGOSINE Multiple languages Urology & Nephrology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12529