Reverse pharmacological effect of loop diuretics and altered rBSC1 expression in rats with lithium nephropathy

Mari Michimata, Sayuri Fujita, Tsutomu Araki, Kazuhiko Mizukami, Itsuro Kazama, Yasuko Muramatsu, Michiko Suzuki, Tokihisa Kimura, Sei Sasaki, Yutaka Imai, Mitsunobu Matsubara

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Background. Renal urinary concentration is associated with enhanced expression of rBSC1, a rat sodium cotransporter, in the thick ascending limb of Henle. Increased expression of rBSC1 was reported recently in nephrogenic diabetes insipidus induced by lithium chloride (Li nephropathy). However, the pathophysiological implication of altered rBSC1 expression has not yet been investigated. Methods. Li nephropathy was induced in rats by an oral administration of 40 mmol lithium/kg dry food. In rats with reduced urinary osmolality to less than 300 mOsm/kg H2O, we examined the expression of rBSC1 mRNA and protein, plasma arginine vasopressin (AVP) and RNA expression of kidney-specific water channel, aquaporin-2 (AQP2), of collecting ducts. Rats with Li nephropathy were treated with furosemide (3 mg/kg body weight), which blocks the activity of rBSC1, and changes in urine concentration, plasma AVP, medullary accumulation of Li ions, and apical AQP2 expression were determined. Results. Rats with Li nephropathy showed increased rBSC1 RNA and protein expression and reduced AQP2 RNA. In these rats, furosemide, which induces dilution of urine and polyuria in normal rats, resulted in a progressive and significant rise in urine osmolality from 167 ± 11 (mean ± SD) at baseline to 450 ± 45 mOsm/kg H2O at three hours after administration, and significant oliguria. In the same rats, plasma AVP decreased significantly from 5.7 to 3.0 pg/mL. In addition, recovery of apical AQP2 expression was noted in a proportion of epithelial cells of the collecting ducts. Although Li+ in the renal medulla was slightly lower in rats with Li nephropathy treated with furosemide, statistical significance was not achieved. Conclusions. Our results suggest that dehydration or high plasma AVP results in an enhanced rBSC1 expression in Li nephropathy, and that rBSC1 expression is closely associated with the adverse effects of Li ions on collecting duct function.

Original languageEnglish
Pages (from-to)165-171
Number of pages7
JournalKidney international
Volume63
Issue number1
DOIs
Publication statusPublished - 2003

Keywords

  • Collecting duct
  • Furosemide
  • Sodium transport
  • Thick ascending limb of Henle
  • Water channel
  • cAMP

ASJC Scopus subject areas

  • Nephrology

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