Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla.
Chloroquine, a widely used anti-malaria drug, has gained popularity for the treatment of rheumatoid arthritis, systemic lupus erythematosus (SLE), and human immunodeficiency virus (HIV). Unfortunately, chloroquine may also negatively impact renal function for patients whose fluid and electrolyte homeostasis is already compromised by diseases. Chronic administration of chloroquine also results in polyuria, which may be explained by suppression of the antidiuretic response of vasopressin. Several of the transporters responsible for concentrating urine are vasopressin-sensitive including the urea transporters UT-A1 and UT-A3, the water channel aquaporin-2 (AQP2), and the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). To examine the effect of chloroquine on these transporters, Sprague-Dawley rats received daily subcutaneous injections of 80 mg·kg(-1)·day(-1) of chloroquine for 4 days. Twenty-four hour urine output was twofold higher, and urine osmolality was decreased by twofold in chloroquine-treated rats compared with controls. Urine analysis of treated rats detected the presence chloroquine as well as decreased urine urea and cAMP levels compared with control rats. Western blot analysis showed a downregulation of AQP2 and NKCC2 transporters; however, UT-A1 and UT-A3 abundances were unaffected by chloroquine treatment. Immunohistochemistry showed a marked reduction of UT-A1 and AQP2 in the apical membrane in inner medullary collecting ducts of chloroquine-treated rats. In conclusion, chloroquine-induced polyuria likely occurs as a result of lowered cAMP production. These findings suggest that chronic chloroquine treatment would exacerbate the already compromised fluid homeostasis observed in diseases like chronic kidney disease.
Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Tobias N
TN
von Bergen
Mitsi A
MA
Blount
D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D002738:Chloroquine / Q000009:adverse effects* / Q000652:urine; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism*; D015536:Down-Regulation; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007671:Kidney Concentrating Ability / Q000187:drug effects*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D009994:Osmolar Concentration; D011141:Polyuria / Q000139:chemically induced*; D051381:Rats; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D014508:Urea / Q000652:urine; D000096982:Urea Transporters
D051399:Aquaporin 2; D002738:Chloroquine; D000242:Cyclic AMP; D026901:Membrane Transport Proteins; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014508:Urea; D000096982:Urea Transporters; C496025:Aqp2 protein, rat; C578714:SLC12A1 protein, human; C578716:Slc12a1 protein, rat