title: Down-regulation of Na+ transporters and AQP2 is responsible for acyclovir-induced polyuria and hypophosphatemia.
abstract: BACKGROUND
  Acyclovir (ACY) is a useful therapeutic agent for the systemic treatment of herpes virus infection. An increase in urinary phosphate excretion and polyuria has been described. The objective of this study was to analyze the exact mechanism of the urinary-concentrating dysfunction and the increase in phosphaturia associated with ACY.
  
  
  METHODS
  We first analyzed 7 (adult and pediatric) non-AIDS cases of encephalitis receiving 15 mg/kg bw/d of intravenous ACY. Fractional phosphate and sodium excretion, urinary potassium volume, and plasma phosphate concentrations were analyzed. Additional studies in rats treated with intraperitoneal ACY (100 mg/kg bw) were also conducted. Animals were maintained in metabolic cages and 24-hour urine samples were collected to measure volume, osmolality, and sodium/potassium/phosphate excretion. Treated rats were also evaluated after 24 hours and 48 hours of water deprivation. Northern hybridization and semiquantitative immunoblotting were performed to evaluate (in both control and treated animals) expression of the cotransporters Na-Pi type IIa (Na-Pi-IIa) and Na-K-2Cl (NKCC2). Semiquantitative immunoblotting was carried out in the kidneys of ACY rats and control rats in order to analyze aquaporin 2 (AQP2) protein expression.
  
  
  RESULTS
  Patients started on ACY developed polyuria and hyperphosphatemia after 48 hours. In rats, ACY-induced hyperphosphaturia and hypophosphatemia were accompanied by increased excretion of sodium, potassium, and magnesium, increased urine output, lower urinary osmolality, and a partial urinary concentrating defect. Concurrent downregulation of Na-Pi-IIa and NKCC2 expression was observed. There was also a decrease in medullar expression of the AQP2 collecting duct water channel.
  
  
  CONCLUSIONS
  Downregulation of Na-Pi-IIa appears to play a crucial role in the downregulation of ACY-induced hyperphosphaturia. The accompanying polyuria and urinary-concentrating defect can in part be explained by the downregulation of NKCC2 and AQP2.
authors.affiliation: Department of Nephrology, Laboratory of Basic Research, University of São Paulo School of Medicine, São Paulo, Brazil. luciacan@usp.br
authors.forename: Lúcia
authors.initials: L
authors.lastname: Andrade
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Rebouças
authors.forename: Antonio Carlos
authors.initials: AC
authors.lastname: Seguro
mesh_terms: D000212:Acyclovir / Q000009:adverse effects*; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects*; D051399:Aquaporin 2; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000097:blood; D002648:Child; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017674:Hypophosphatemia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007671:Kidney Concentrating Ability / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008274:Magnesium / Q000097:blood; D008297:Male; D009994:Osmolar Concentration; D010710:Phosphates / Q000097:blood / Q000652:urine; D011141:Polyuria / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1; D014556:Urine; D014867:Water / Q000378:metabolism
chemical_list: C496023:AQP2 protein, human; D000998:Antiviral Agents; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D020346:Aquaporins; D010710:Phosphates; D012333:RNA, Messenger; C578714:SLC12A1 protein, human; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014867:Water; D012964:Sodium; D008274:Magnesium; D011188:Potassium; D002118:Calcium; D000212:Acyclovir