Work

Upregulation of aquaporin-2 water channel expression in chronic heart failure rat.

Year: 1997

Type: article

Abstract: Aquaporin-2 (AQP2) mediates vasopressin-regulated collecting duct water permeability.Chronic heart failure (CHF) is characterized by abnormal renal water retention.We hypothetized that upregulation of aquaporin-2 water channel could account for the water retention in CHF.Male rats underwent either a left coronary artery ligation, a model of CHF, or were sham operated.31-33 d after surgery, mean arterial pressure (MAP) and cardiac output were measured in conscious animals, and the animals were killed 24 h later.Cardiac output (CO) and plasma osmolality were significantly decreased and plasma vasopressin increased in the CHF as compared to the sham-operated rats.Both mRNA and protein AQP2 were significantly increased in the kidneys of the CHF rats.The effect of oral administration of a nonpeptide V2 vasopressin receptor antagonist, OPC 31260, was therefore investigated.OPC 31260 induced a significant increase in diuresis, decrease in urinary osmolality, and rise in plasma osmolality in the OPC 31260treated CHF rats as compared to untreated CHF rats.The mRNA and protein AQP2 were significantly diminished in both cortex and inner medulla of the treated CHF rats.In conclusion, an early upregulation of AQP2 is present in CHF rats and this upregulation is inhibited by the administration of a V2 receptor antagonist.The results indicate a major role for vasopressin in the upregulation of AQP2 water channels and water retention in experimental CHF in the rat.( J. Clin.Invest.1997.99:1500-1505.)Key words: vasopressin • vasopressin-receptor antagonists • hyponatremia • water excretion • edema lntroductionWater retention is characteristic of advanced congestive heart failure (CHF) 1 (1).Moreover, hyponatremia is a well-defined predictor of mortality of heart failure (2, 3).Plasma arginine vasopressin (AVP) concentrations have been found to be elevated in hyponatremic patients with CHF (4) and are not suppressed during an acute water loading (5).The hypothalamic messenger RNA for vasopressin has also been shown to be increased in experimental CHF (6).Recently, the aquaporin-2 (AQP2) water channel has been cloned and located in the principal cells of the collecting duct (7).Regulation of water transport across the renal principal cells depends on two mechanisms.( a ) The rapid action of AVP to increase the water permeability of the apical membrane of principal cells by translocating the AQP2 water channels from cytosolic vesicles to the plasma membranes (8).This short-term effect is mediated by the V2 receptor-dependent increase of adenosine 3 Ј 5 Ј -cAMP and may involve cAMP-dependent phosphorylation of AQP2 (9).( b ) Long-term regulation of collecting duct water permeability is characterized by a increase in AQP2 mRNA and protein content during fluid restriction and AVP infusion into diabetes insipidus (Brattelboro) rats (10-12).Therefore, in a pathophysiological situation such as CHF, a chronic increase in plasma AVP concentration could upregulate the expression of AQP2.This study was therefore undertaken to determine the AQP2 expression in a rat model of CHF induced by the ligation of the left coronary artery.For this purpose, AQP2 mRNA and protein were compared between sham-operated and decompensated CHF rats.Next the effect of a nonpeptide V2 vasopressin receptor antagonist (OPC 31260) was examined in sham-operated and CHF rats on AQP2 mRNA and protein, water excretion, and plasma osmolality. MethodsMale Sprague-Dawley rats (200-250 g; Sasco, Omaha, NE) were used for all experiments.The rats were housed in a controlled environment and kept in filter-top microisolators.Animals were allowed free access to tap water and food (ProLab 3000; Agway Inc., Syracuse, NY) that contained 0.44% sodium and 22.5% protein.The protocol was approved by the University of Colorado Health Sciences Center Animal Care and Use Committee.

Source: Journal of Clinical Investigation

DOI: 10.1172/jci119312