Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla

Abstract

<jats:p>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<jats:sup>+</jats:sup>-K<jats:sup>+</jats:sup>-2Cl<jats:sup>−</jats:sup>cotransporter (NKCC2). To examine the effect of chloroquine on these transporters, Sprague-Dawley rats received daily subcutaneous injections of 80 mg·kg<jats:sup>−1</jats:sup>·day<jats:sup>−1</jats:sup>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.</jats:p>

Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target

“…It has been demonstrated in in vitro and in vivo studies on the rat inner medullary collecting ducts that chloroquine inhibits both basal and arginine vasopressin (AVP)-induced cAMP production. 30, 31 Our data show a greater reduction in cholangiocyte cAMP levels when the drugs are used together than when they are used alone. Thus, it appears that both drugs via different mechanisms affect cAMP signaling.…”

Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus

“…Consequently, protein abundance of AQP2 is increased as a regulatory mechanism to long periods of water deprivation and/or high circulating levels of vasopressin [37] . Several animal models of acquired NDI including hypokalemia, hypercalcemia, ureteral obstruction, chloroquine and lithium nephrotoxicity have decreased AQP2 expression in the inner medulla [23] , [38] – [40] ; hence the need to understand the transcriptional regulation of the AQP2 gene. It is generally accepted that the cAMP-mediated regulation of AQP2 gene transcription is mediated by CREB binding to a documented functional CRE element [41] .…”

Systemic toxicity of chloroquine and hydroxychloroquine: prevalence, mechanisms, risk factors, prognostic and screening possibilities

“…Taking 4-AQ is associated with the onset of chronic renal failure [78,143]. 4-AQ-induced polyuria is also described [144].…”

“…4-AQ-induced polyuria is multifactorial. On the one hand, 4-AQ downregulates the water channel aquaporin-2 and the Na + -K + -2Cl − -cotransporter (NKCC), causing urinary sodium loss and an increase in diuresis [144] . On the other hand, it is showed that CQ modulates the synthesis of plasma arginine vasopressin [151 , 152] and its effect on the kidney [153] , disrupting the urine concentration mechanisms.…”