Extrarenal Phenotypes of the UT-B Knockout Mouse

Abstract

The urea transporter UT-B is expressed in multiple tissues including erythrocytes, kidney, brain, heart, liver, colon, bone marrow, spleen, lung, skeletal muscle, bladder, prostate, and testis in mammals. Phenotype analysis of UT-B-null mice has confirmed that UT-B deletion results in a urea-selective urine-concentrating defect (see Chap. 9 ). The functional significance of UT-B in extrarenal tissues studied in the UT-B-null mouse is discussed in this chapter. UT-B-null mice present depression-like behavior with urea accumulation and nitric oxide reduction in the hippocampus. UT-B deletion causes a cardiac conduction defect, and TNNT2 and ANP expression changes in the aged UT-B-null heart. UT-B also plays a very important role in protecting bladder urothelium from DNA damage and apoptosis by regulating the urea concentration in urothelial cells. UT-B functional deficiency results in urea accumulation in the testis and early maturation of the male reproductive system. These results show that UT-B is an indispensable transporter involved in maintaining physiological functions in different tissues.

Physiological functions of urea transporter B

“…The frequency of UT-B efficiency is significantly higher than that of other transporters. Given that urea concentrations in the bladder of UT-B-/- mice are several times higher than those of wild-type mice, they can induce cell cycle arrest and apoptosis [36, 72, 92]. In the urothelium of UT-B-/- bladder, the decreased BcL-2 expression and increased caspase-3 and Bax expression, together with downregulated ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which promotes cell proliferation and enhances anti-apoptotic signaling pathway, may underlie the mechanisms by which high concentrations of urea cause urothelial cell apoptosis.…”

“…L-arginine is cleaved by arginase to produce urea and ornithine, which can be preferably converted into polyamines by ornithine decarboxylase (ODC). Interestingly, the arginase I expression is significantly downregulated in urothelial cells of UT-B-/- mice [92]. This will reduce the production of ornithine and polyamine.…”

“…Furthermore, UT-B-/- mice had higher body weights than wild-type mice, and earlier spermatogenesis and reproductive system maturation. However, there is no abnormality in the integrity of spermatogenic epithelial cells, sperm morphology or distribution, and the tubular and lumen diameters of the spermatogenic tubules in UT-B-/- mice [92].…”

“…FSH can through its FSHR stimulates ABP expression in Sertoli cells, which is important for the maintenance of sperm number. Actually, significantly higher levels of FSHR and ABP expression are detected in the testis of UT-B-/- mice at 10 days of age, accompanied by accelerating sperm formation and reproductive system maturation [92]. These suggest that UT-B-related urea concentrations may contribute to the development of Sertoli cells in the reproductive system of mice [25, 91].…”

Functional inhibition of urea transporter UT-B enhances endothelial-dependent vasodilatation and lowers blood pressure via L-arginine-endothelial nitric oxide synthase-nitric oxide pathway

“…UT-A subfamily has 6 members (UT-A1~UT-A6), most of which are expressed in kidney and play an important role in urine concentrating mechanism 2 . UT-B subfamily has only one member, which has a discrete tissue distribution with high expression in erythrocyte 3 , renal descending vasa recta (DVR) 4 , brain astrocyte 5 , testis Sertoli cell 6 , urothelial cell in bladder and ureter 7 8 , endothelial cell in blood vessel 9 , etc., suggesting that UT-B may have distinct function specific to its tissue localization.…”