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Author

Kwon, H. Moo
Inflammation and Kidney Disorder Lab
Research Interests
  • TonEBP, Obesity, Cancer, Chronic inflammatory diseases, Brain disorder, Kidney disorders, Genomic instability

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Downregulation of renal sodium transporters and tonicity-responsive enhancer binding protein by long-term treatment with cyclosporin A

Cited 19 times inthomson ciCited 17 times inthomson ci
Title
Downregulation of renal sodium transporters and tonicity-responsive enhancer binding protein by long-term treatment with cyclosporin A
Author
Lim, Sun WooAhn, Kyung OhkSheen, Mee RieJeon, Un SilKim, JinYang, Chul WooKwon, H. Moo
Keywords
THICK ASCENDING LIMB; UREA TRANSPORTERS; COLLECTING DUCT; EXPRESSION; COTRANSPORTER; CELLS; HYPERTONICITY; CALCINEURIN; MECHANISM; FIBROSIS
Issue Date
200702
Publisher
AMER SOC NEPHROLOGY
Citation
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, v.18, no.2, pp.421 - 429
Abstract
Tonicity-responsive enhancer binding protein (TonEBP) is a transcriptional activator that is regulated by ambient tonicity. TonEBP protects the-rental medulla from the deleterious effects of hyperosmolality and regulates the urinary concentration by stimulating aquaporin-2 and urea transporters. The therapeutic use of cyclosporin A (CsA) is limited by nephrotoxicity that is manifested by reduced GFR, fibrosis, and tubular defects, including reduced urinary concentration. It was reported recently that long-term CsA treatment was associated with decreased renal expression of TonEBP target genes, including aquaporin-2, urea transporter, and aldose reductase. This study tested the hypothesis that long-term CsA treatment reduces the salinity/tonicity of the renal medullary interstitium as a result of inhibition of active sodium transporters, leading to downregulation of TonEBP. CsA treatment for 7 d did not affect TonEBP or renal function. Whereas expression of sodium transporters was altered, the medullary tonicity seemed unchanged. Conversely, 28 d of CsA treatment led to downregulation of TonEBP and overt nephrotoxicity. The downregulation of TonEBP involved reduced expression, cytoplasmic shift, and reduced transcription of its target genes. This was associated with reduced expression of active sodium transporters-sodium/potassium/chloride transporter type 2 (NKCC2), sodium/chloride transporter, and Na+,K+-ATPase-along with increased sodium excretion and reduced urinary concentration. Infusion of vasopressin restored the expression of NKCC2 in the outer medulla as well as the expression and the activity of TonEBP. It is concluded that the downregulation of TonEBP in the setting of long-term CsA administration is secondary to the reduced tonicity of the renal medullary interstitium.
URI
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DOI
http://dx.doi.org/10.1681/ASN.2006060664
ISSN
1046-6673
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