Localization of the urea transporter UT-B protein in human and rat erythrocytes and tissues

Timmer, Richard T.; Klein, Janet D.; Bagnasco, Serena M.; Doran, John; Verlander, Jill W.; Gunn, Robert B.; Sands, Jeff M.

doi:10.1152/ajpcell.2001.281.4.c1318

Cited by 110 publications

(132 citation statements)

References 31 publications

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“…SLC14A1, which encodes the urea transporter UTB (28)(29)(30), was the most significantly differentially expressed transcript in the RNA-seq study of the OVT73 sheep striatum. SLC14A1 was subsequently found to be elevated by >twofold in two subregions of the OVT73 striatum and in the motor cortex and cerebellum.…”

Section: Discussionmentioning

confidence: 99%

Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

Handley

Reid

Bräuning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.is a dominantly inherited neurological disorder typified by chorea, psychological disturbance, and dementia. The symptoms progress and result in premature death, typically 10-15 y after onset. Currently no available treatment can delay or prevent the onset of HD. The gene responsible, Huntingtin (HTT), is ubiquitously expressed and encodes the large and multifunctional huntingtin protein.The disease-causing mutation is an expanded CAG repeat in exon 1 of HTT, coding for a glutamine tract within the protein (1). The disease-causing repeat lower length threshold is 36 units and is fully penetrant at 40 units and above (2, 3). There is an inverse correlation between expanded CAG repeat size and age at onset of symptoms (4-6). Although the mutation is well defined, the pathogenic process is not sufficiently understood to enable effective treatment. The majority of HD research focuses on the brain where there is characteristic neuropathology, primarily atrophy of the striatum (7).Alongside the striking neurological phenotype of HD, there is a generalized metabolic disruption. HD mutation carriers weigh less on average than non-HD individuals (8). Weight loss begins presymptomatically (9, 10), and in symptomatic individuals, energy expenditure far exceeds that utilized in movement, despite high calor...

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Section: Discussionmentioning

confidence: 99%

Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

Handley

Reid

Bräuning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…2) (46). These vascular bundles are particularly well defined in the outer medulla and in the outer ϳ50%, by length, of the inner medulla.…”

Section: Two Lateral Regions Of the Inner Medullamentioning

confidence: 95%

Architecture of the human renal inner medulla and functional implications

Wei

Rosen

Dantzler

et al. 2015

American Journal of Physiology-Renal Physiology

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The architecture of the inner stripe of the outer medulla of the human kidney has long been known to exhibit distinctive configurations; however, inner medullary architecture remains poorly defined. Using immunohistochemistry with segment-specific antibodies for membrane fluid and solute transporters and other proteins, we identified a number of distinctive functional features of human inner medulla. In the outer inner medulla, aquaporin-1 (AQP1)-positive long-loop descending thin limbs (DTLs) lie alongside descending and ascending vasa recta (DVR, AVR) within vascular bundles. These vascular bundles are continuations of outer medullary vascular bundles. Bundles containing DTLs and vasa recta lie at the margins of coalescing collecting duct (CD) clusters, thereby forming two regions, the vascular bundle region and the CD cluster region. Although AQP1 and urea transporter UT-B are abundantly expressed in long-loop DTLs and DVR, respectively, their expression declines with depth below the outer medulla. Transcellular water and urea fluxes likely decline in these segments at progressively deeper levels. Smooth muscle myosin heavy chain protein is also expressed in DVR of the inner stripe and the upper inner medulla, but is sparsely expressed at deeper inner medullary levels. In rodent inner medulla, fenestrated capillaries abut CDs along their entire length, paralleling ascending thin limbs (ATLs), forming distinct compartments (interstitial nodal spaces; INSs); however, in humans this architecture rarely occurs. Thus INSs are relatively infrequent in the human inner medulla, unlike in the rodent where they are abundant. UT-B is expressed within the papillary epithelium of the lower inner medulla, indicating a transcellular pathway for urea across this epithelium.

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“…In addition to the DVR, UT-B protein is expressed in red blood cells (RBC) (63) and contributes to their high urea permeability. This high urea permeability is thought to have a physiological role; rapid urea transport may help to preserve the osmotic stability and deformability of the RBC (64) and thereby help to prevent dissipation of the urea gradient in the renal medulla (discussed in reference [65]) and overall concentrating ability.…”

Section: Urea Recyclingmentioning

confidence: 99%

Urea and Renal Function in the 21st Century

Fenton¹,

Knepper²

2007

Journal of the American Society of Nephrology

115

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Since the turn of the 21st century, gene knockout mice have been created for all major urea transporters that are expressed in the kidney: the collecting duct urea transporters UT-A1 and UT-A3, the descending thin limb isoform UT-A2, and the descending vasa recta isoform UT-B. This article discusses the new insights that the results from studies in these mice have produced in the understanding of the role of urea in the urinary concentrating mechanism and kidney function. Following is a summary of the major findings: (1) Urea accumulation in the inner medullary interstitium depends on rapid transport of urea from the inner medullary collecting duct (IMCD) lumen via UT-A1 and/or UT-A3; (2) as proposed by Robert Berliner and colleagues in the 1950s, the role of IMCD urea transporters in water conservation is to prevent a urea-induced osmotic diuresis; (3) the absence of IMCD urea transport does not prevent the concentration of NaCl in the inner medulla, contrary to what would be predicted from the passive countercurrent multiplier mechanism in the form proposed by Kokko and Rector and Stephenson; (4) deletion of UT-B (vasa recta isoform) has a much greater effect on urinary concentration than deletion of UT-A2 (descending limb isoform), suggesting that the recycling of urea between the vasa recta and the renal tubules quantitatively is less important than classic countercurrent exchange; and (5) urea reabsorption from the IMCD and the process of urea recycling are not important elements of the mechanism of protein-induced increases in GFR. In addition, the clinical relevance of these studies is discussed, and it is suggested that inhibitors that specifically target collecting duct urea transporters have the potential for clinical use as potassium-sparing diuretics that function by creation of urea-dependent osmotic diuresis.

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Localization of the urea transporter UT-B protein in human and rat erythrocytes and tissues

Cited by 110 publications

References 31 publications

Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

Architecture of the human renal inner medulla and functional implications

Urea and Renal Function in the 21st Century

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