Inorganic sulfate is required for numerous functions in mammalian physiology, and its circulating levels are proposed to be maintained by the Na ؉ -SO 4 2؊ cotransporter, (NaSi-1). To determine the role of NaSi-1 in sulfate homeostasis and the physiological consequences in its absence, we have generated a mouse lacking a functional NaSi-1 gene, Nas1. Serum sulfate concentration was reduced by >75% in Nas1 ؊/؊ mice when compared with Nas1 ؉/؉ mice. Nas1 ؊/؊ mice exhibit increased urinary sulfate excretion, reduced renal and intestinal Na ؉ -SO 4 2؊ cotransport, and a general growth retardation. Nas1 ؊/؊ mouse body weight was reduced by >20% when compared with Nas1 ؉/؉ and Nas1 ؉/؊ littermates at 2 weeks of age and remained so throughout adulthood. Nas1 ؊/؊ females had a lowered fertility, with a 60% reduction in litter size. Spontaneous clonic seizures were observed in Nas1 ؊/؊ mice from 8 months of age. These data demonstrate NaSi-1 is essential for maintaining sulfate homeostasis, and its expression is necessary for a wide range of physiological functions.I norganic sulfate (SO 4 2Ϫ ) is an abundant anion in mammalian plasma and is essential for numerous physiological functions (1). SO 4 2Ϫ conjugation is an important step in the biotransformation of xenobiotics such as steroids, antiinflammatory agents, adrenergic stimulants and blockers, analgesics, and, in most cases, leads to an increase in their urinary excretion (2). SO 4 2Ϫ is also required for the activation of many endogenous compounds such as heparin, heparan sulfate, dermatan sulfate, and bile acids (3). In addition, sulfation of structural components such as glycosaminoglycans and cerebroside sulfate is essential for the maintenance of normal structure and function of tissues (4). Disturbances of SO 4 2Ϫ metabolism and transport have been associated with human syndromes and diseases, including metachromatic leukodystrophy, Hunter's syndrome, Morquio's syndrome, Maroteaux-Lamy syndrome, multiple-sulfohydrolase deficiency, and osteochondrodysplasias (5, 6). However, despite its importance in the body, SO 4 2Ϫ levels are rarely measured in a clinical setting and there remains areas in which knowledge of its significance is still lacking, or is at most, minimal.In humans, SO 4 2Ϫ absorption is initiated in the small intestine and its homeostasis is proposed to be maintained through renal tubular mechanisms (7). SO 4 2Ϫ is freely filtered in the glomerulus and is actively reabsorbed in the proximal tubule. Renal proximal tubular SO 4 2Ϫ reabsorption is mediated by entry through the brush-border membrane (BBM) by a Na ϩ -SO 4 2Ϫ cotransporter (NaS i -1), and exit through the basolateral membrane by an anion exchanger, Sat-1 (1). The NaS i -1 transporter is expressed primarily in the kidney and intestine (8) and has been proposed to play a major role in maintaining serum SO 4 2Ϫ concentrations within the normal physiological range of 0.33-0.47 mmol͞liter in humans (9-11). In recent years, a growing body of experimental evidence has demonstrated that variou...
Urolithiasis, a condition in which stones are present in the urinary system, including the kidneys and bladder, is a poorly understood yet common disorder worldwide that leads to significant health care costs, morbidity, and work loss. Acetaminophen-induced liver damage is a major cause of death in patients with acute liver failure. Kidney and urinary stones and liver toxicity are disturbances linked to alterations in oxalate and sulfate homeostasis, respectively. The sulfate anion transporter-1 (Sat1; also known as Slc26a1) mediates epithelial transport of oxalate and sulfate, and its localization in the kidney, liver, and intestine suggests that it may play a role in oxalate and sulfate homeostasis. To determine the physiological roles of Sat1, we created Sat1 -/-mice by gene disruption. These mice exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder. Sat1 -/-mice also displayed hypersulfaturia, hyposulfatemia, and enhanced acetaminophen-induced liver toxicity. These data suggest that Sat1 regulates both oxalate and sulfate homeostasis and may be critical to the development of calcium oxalate urolithiasis and hepatotoxicity.
Hypoxanthine-guanine phosphoribosyltransferase (HPRT, EC 2.4.2.8) is a purine salvage enzyme that catalyses the conversion of hypoxanthine and guanine to their respective mononucleotides. Partial deficiency of this enzyme can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes the Lesch-Nyhan syndrome which is characterised by hyperuricaemia, mental retardation, choreoathetosis and compulsive self-mutilation. The HPRT-encoding gene is located on the X chromosome in the region q26-q27 and consists of nine exons and eight introns totalling 57 kb. This gene is transcribed to produce an mRNA of 1.6 kb, which contains a protein encoding region of 654 nucleotides. With the advent of increasingly refined techniques of molecular biology, it has been possible to study the HPRT gene of individuals with a deficiency in HPRT activity to determine the genetic basis of the enzyme deficiency. Many different mutations throughout the coding region have been described, but in the absence of precise information on the three-dimensional structure of the HPRT protein, it remains difficult to determine any consistent correlation between the structure and function of the enzyme.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.