Mice with targeted disruption of the acyl-CoA binding protein display attenuated urine concentrating ability and diminished renal aquaporin-3 abundance

Abstract

The acyl-CoA binding protein (ACBP) is a small intracellular protein that specifically binds and transports medium to long-chain acyl-CoA esters. Previous studies have shown that ACBP is ubiquitously expressed but found at particularly high levels in lipogenic cell types as well as in many epithelial cells. Here we show that ACBP is widely expressed in human and mouse kidney epithelium, with the highest expression in the proximal convoluted tubules. To elucidate the role of ACBP in the renal epithelium, mice with targeted disruption of the ACBP gene (ACBP−/−) were used to study water and NaCl balance as well as urine concentrating ability in metabolic cages. Food intake and urinary excretion of Na+and K+did not differ between ACBP−/−and+/+mice. Interestingly, however, water intake and diuresis were significantly higher at baseline in ACBP−/−mice compared with that of+/+mice. Subsequent to 20-h water deprivation, ACBP−/−mice exhibited increased diuresis, reduced urine osmolality, elevated hematocrit, and higher relative weight loss compared with+/+mice. There were no significant differences in plasma concentrations of renin, corticosterone, and aldosterone between mice of the two genotypes. After water deprivation, renal medullary interstitial fluid osmolality and concentrations of Na+, K+, and urea did not differ between genotypes and cAMP excretion was similar. Renal aquaporin-1 (AQP1), -2, and -4 protein abundances did not differ between water-deprived+/+and ACBP−/−mice; however, ACBP−/−mice displayed increased apical targeting of pS256-AQP2. AQP3 abundance was lower in ACBP−/−mice than in+/+control animals. Thus we conclude that ACBP is necessary for intact urine concentrating ability. Our data suggest that the deficiency in urine concentrating ability in the ACBP−/−may be caused by reduced AQP3, leading to impaired efflux over the basolateral membrane of the collecting duct.