Altered expression of selected genes in kidney of rats with lithium-induced NDI

Aleksandra Rojek, Jakob Nielsen, Heddwen L Brooks, Hong Gong, Young Hee Kim, Tae Hwan Kwon, Jørgen Frøkiær, Søren Nielsen

Research output: Contribution to journalArticle

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Abstract

Lithium treatment is associated with development of nephrogenic diabetes insipidus, caused in part by downregulation of collecting duct aquaporin-2 (AQP2) and AQP3 expression. In the present study, we carried out cDNA microarray screening of gene expression in the inner medulla (IM) of lithium-treated and control rats, and selected genes were then investigated at the protein level by immunoblotting and/or immunohistochemistry. The following genes exhibited significantly altered transcription and mRNA expression levels, and these were compatible with the changes in protein expression. 11β-Hydroxysteroid dehydrogenase type 2 protein expression in the IM was markedly increased (198 ± 25% of controls, n = 6), and immunocytochemistry demonstrated an increased labeling of IM collecting duct (IMCD) principal cells. This indicated altered renal mineralocorticoid/glucocorticoid responses in lithium-treated rats. The inhibitor of cyclin-dependent kinases p27 (KIP) protein expression was significantly decreased or undetectable in the IMCD cells, pointing to increased cellular proliferation and remodeling. Heat shock protein 27 protein expression was decreased in the IM (64 ± 6% of controls, n = 6), likely to be associated with the decreased medullary osmolality in lithium-treated rats. Consistent with this, lens aldose reductase protein expression was markedly decreased in the IM (16 ± 2% of controls, n = 6), and immunocytochemistry revealed decreased expression in the thin limb cells in the middle and terminal parts of the IM. Ezrin protein expression was upregulated in the IM (158 ± 16% of controls, n = 6), where it was predominantly expressed in the apical and cytoplasmic domain of the IMCD cells. Increased ezrin expression indicated remodeling of the actin cytoskeleton and/or altered regulation of IMCD transporters. In conclusion, the present study demonstrates changes in gene expression not only in the collecting duct but also in the thin limb of the loop of Henle in the IM, and several of these genes are linked to altered sodium and water reabsorption, cell cycling, and changes in interstitial osmolality.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume288
Issue number6 57-6
DOIs
StatePublished - Jun 2005

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Lithium
Kidney
Gene Expression
Proteins
Immunohistochemistry
Osmolar Concentration
Cyclin-Dependent Kinase Inhibitor Proteins
Extremities
Aquaporin 2
Nephrogenic Diabetes Insipidus
11-beta-Hydroxysteroid Dehydrogenases
HSP27 Heat-Shock Proteins
Cyclin-Dependent Kinase Inhibitor p27
Genes
Loop of Henle
Aldehyde Reductase
Mineralocorticoids
Oligonucleotide Array Sequence Analysis
Actin Cytoskeleton
Immunoblotting

Keywords

  • 11β-hydroxysteroid dehydrogenase type 2
  • Aldose reductase
  • Heat shock protein 27
  • Inhibitor of cyclin-dependent kinases p27
  • Nephrogenic diabetes insipidus
  • Urine concentration

ASJC Scopus subject areas

  • Physiology

Cite this

Altered expression of selected genes in kidney of rats with lithium-induced NDI. / Rojek, Aleksandra; Nielsen, Jakob; Brooks, Heddwen L; Gong, Hong; Kim, Young Hee; Kwon, Tae Hwan; Frøkiær, Jørgen; Nielsen, Søren.

In: American Journal of Physiology - Renal Physiology, Vol. 288, No. 6 57-6, 06.2005.

Research output: Contribution to journalArticle

Rojek, Aleksandra ; Nielsen, Jakob ; Brooks, Heddwen L ; Gong, Hong ; Kim, Young Hee ; Kwon, Tae Hwan ; Frøkiær, Jørgen ; Nielsen, Søren. / Altered expression of selected genes in kidney of rats with lithium-induced NDI. In: American Journal of Physiology - Renal Physiology. 2005 ; Vol. 288, No. 6 57-6.
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abstract = "Lithium treatment is associated with development of nephrogenic diabetes insipidus, caused in part by downregulation of collecting duct aquaporin-2 (AQP2) and AQP3 expression. In the present study, we carried out cDNA microarray screening of gene expression in the inner medulla (IM) of lithium-treated and control rats, and selected genes were then investigated at the protein level by immunoblotting and/or immunohistochemistry. The following genes exhibited significantly altered transcription and mRNA expression levels, and these were compatible with the changes in protein expression. 11β-Hydroxysteroid dehydrogenase type 2 protein expression in the IM was markedly increased (198 ± 25{\%} of controls, n = 6), and immunocytochemistry demonstrated an increased labeling of IM collecting duct (IMCD) principal cells. This indicated altered renal mineralocorticoid/glucocorticoid responses in lithium-treated rats. The inhibitor of cyclin-dependent kinases p27 (KIP) protein expression was significantly decreased or undetectable in the IMCD cells, pointing to increased cellular proliferation and remodeling. Heat shock protein 27 protein expression was decreased in the IM (64 ± 6{\%} of controls, n = 6), likely to be associated with the decreased medullary osmolality in lithium-treated rats. Consistent with this, lens aldose reductase protein expression was markedly decreased in the IM (16 ± 2{\%} of controls, n = 6), and immunocytochemistry revealed decreased expression in the thin limb cells in the middle and terminal parts of the IM. Ezrin protein expression was upregulated in the IM (158 ± 16{\%} of controls, n = 6), where it was predominantly expressed in the apical and cytoplasmic domain of the IMCD cells. Increased ezrin expression indicated remodeling of the actin cytoskeleton and/or altered regulation of IMCD transporters. In conclusion, the present study demonstrates changes in gene expression not only in the collecting duct but also in the thin limb of the loop of Henle in the IM, and several of these genes are linked to altered sodium and water reabsorption, cell cycling, and changes in interstitial osmolality.",
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AU - Kwon, Tae Hwan

AU - Frøkiær, Jørgen

AU - Nielsen, Søren

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AB - Lithium treatment is associated with development of nephrogenic diabetes insipidus, caused in part by downregulation of collecting duct aquaporin-2 (AQP2) and AQP3 expression. In the present study, we carried out cDNA microarray screening of gene expression in the inner medulla (IM) of lithium-treated and control rats, and selected genes were then investigated at the protein level by immunoblotting and/or immunohistochemistry. The following genes exhibited significantly altered transcription and mRNA expression levels, and these were compatible with the changes in protein expression. 11β-Hydroxysteroid dehydrogenase type 2 protein expression in the IM was markedly increased (198 ± 25% of controls, n = 6), and immunocytochemistry demonstrated an increased labeling of IM collecting duct (IMCD) principal cells. This indicated altered renal mineralocorticoid/glucocorticoid responses in lithium-treated rats. The inhibitor of cyclin-dependent kinases p27 (KIP) protein expression was significantly decreased or undetectable in the IMCD cells, pointing to increased cellular proliferation and remodeling. Heat shock protein 27 protein expression was decreased in the IM (64 ± 6% of controls, n = 6), likely to be associated with the decreased medullary osmolality in lithium-treated rats. Consistent with this, lens aldose reductase protein expression was markedly decreased in the IM (16 ± 2% of controls, n = 6), and immunocytochemistry revealed decreased expression in the thin limb cells in the middle and terminal parts of the IM. Ezrin protein expression was upregulated in the IM (158 ± 16% of controls, n = 6), where it was predominantly expressed in the apical and cytoplasmic domain of the IMCD cells. Increased ezrin expression indicated remodeling of the actin cytoskeleton and/or altered regulation of IMCD transporters. In conclusion, the present study demonstrates changes in gene expression not only in the collecting duct but also in the thin limb of the loop of Henle in the IM, and several of these genes are linked to altered sodium and water reabsorption, cell cycling, and changes in interstitial osmolality.

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