title: Reverse pharmacological effect of loop diuretics and altered rBSC1 expression in rats with lithium nephropathy.
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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Medicine and Pharmaceutical Science, Sendai, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Michimata
authors.forename: Sayuri
authors.initials: S
authors.lastname: Fujita
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Araki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mizukami
authors.forename: Itsuro
authors.initials: I
authors.lastname: Kazama
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Muramatsu
authors.forename: Michiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Tokihisa
authors.initials: T
authors.lastname: Kimura
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Imai
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Matsubara
mesh_terms: D000818:Animals; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000235:genetics; D001127:Arginine Vasopressin / Q000097:blood; D003681:Dehydration / Q000503:physiopathology; D004232:Diuretics / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology*; D015870:Gene Expression; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007685:Kidney Tubules, Collecting / Q000502:physiology; D008094:Lithium; D008138:Loop of Henle / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064466:Solute Carrier Family 12, Member 1; D014556:Urine
chemical_list: C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D004232:Diuretics; D012333:RNA, Messenger; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D001127:Arginine Vasopressin; D005665:Furosemide; D008094:Lithium