RNA-Seq and protein mass spectrometry in microdissected kidney tubules reveal signaling processes initiating lithium-induced nephrogenic diabetes insipidus

Chih Chien Sung, Lihe Chen, K. Limbutara, Hyun Jun Jung, Gabrielle G. Gilmer, Chin Rang Yang, Shih Hua Lin, Sookkasem Khositseth, Chung Lin Chou, Mark A. Knepper

Research output: Contribution to journalArticle

Abstract

Lithium salts, used for treating bipolar disorder, frequently induce nephrogenic diabetes insipidus (NDI) thereby limiting therapeutic success. NDI is associated with loss of expression of the gene coding for the molecular water channel, aquaporin-2, in the renal collecting duct (CD). Here, we use systems biology methods in a well-established rat model of lithium-induced NDI to identify signaling pathways activated at the onset of polyuria. Using single-tubule RNA-Seq, full transcriptomes were determined in microdissected cortical collecting ducts (CCDs) of rats after 72 hours without or with initiation of lithium chloride administration. Transcriptome-wide changes in mRNA abundances were mapped to gene sets associated with curated canonical signaling pathways, showing evidence for activation of NF-κB signaling with induction of genes coding for multiple chemokines and most components of the Major Histocompatibility Complex Class I antigen-presenting complex. Administration of anti-inflammatory doses of dexamethasone to lithium chloride–treated rats countered the loss of aquaporin-2. RNA-Seq also confirmed prior evidence of a shift from quiescence into the cell cycle with arrest. Time course studies demonstrated an early (12 hour) increase in multiple immediate early response genes including several transcription factors. Protein mass spectrometry in microdissected CCDs provided corroborative evidence and identified decreased abundance of several anti-oxidant proteins. Thus, in the context of prior observations, our study can be best explained by a model in which lithium increases ERK activation leading to induction of NF-κB signaling and an inflammatory-like response that represses Aqp2 transcription.

Original languageEnglish (US)
Pages (from-to)363-377
Number of pages15
JournalKidney International
Volume96
Issue number2
DOIs
StatePublished - Aug 2019
Externally publishedYes

Fingerprint

Nephrogenic Diabetes Insipidus
Kidney Tubules
Lithium
Mass Spectrometry
Aquaporin 2
RNA
Transcriptome
Proteins
Lithium Chloride
Polyuria
Histocompatibility Antigens Class I
Aquaporins
Immediate-Early Genes
Systems Biology
Cell Cycle Checkpoints
Major Histocompatibility Complex
Bipolar Disorder
Chemokines
Oxidants
Dexamethasone

Keywords

  • collecting duct
  • immediate early response
  • NF-κB signaling

ASJC Scopus subject areas

  • Nephrology

Cite this

RNA-Seq and protein mass spectrometry in microdissected kidney tubules reveal signaling processes initiating lithium-induced nephrogenic diabetes insipidus. / Sung, Chih Chien; Chen, Lihe; Limbutara, K.; Jung, Hyun Jun; Gilmer, Gabrielle G.; Yang, Chin Rang; Lin, Shih Hua; Khositseth, Sookkasem; Chou, Chung Lin; Knepper, Mark A.

In: Kidney International, Vol. 96, No. 2, 08.2019, p. 363-377.

Research output: Contribution to journalArticle

Sung, Chih Chien ; Chen, Lihe ; Limbutara, K. ; Jung, Hyun Jun ; Gilmer, Gabrielle G. ; Yang, Chin Rang ; Lin, Shih Hua ; Khositseth, Sookkasem ; Chou, Chung Lin ; Knepper, Mark A. / RNA-Seq and protein mass spectrometry in microdissected kidney tubules reveal signaling processes initiating lithium-induced nephrogenic diabetes insipidus. In: Kidney International. 2019 ; Vol. 96, No. 2. pp. 363-377.
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AU - Gilmer, Gabrielle G.

AU - Yang, Chin Rang

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