Several urate transporters have already been identified but recently, using an approach called genome-wide association scanning, Caulfield and others found that some genetic variants of a human gene called SLC2A9 are more common in people with high serum urate levels than in people with normal levels. SLC2A9 encodes a glucose transporter (a protein that helps to move the sugar glucose through cell membranes) and is highly expressed in the kidney's main urate handling site. Professor Caulfield and his team investigated the possibility that the protein made by the SLC2A9 gene might be a urate transporter and tested whether genetic variations in SLC2A9 might be responsible for the association between serum urate levels and high blood pressure.
The team first expressed SLC2A9 in frog eggs, a type of cell that does not have its own urate transporter. They found that SLC2A9 transported urate about 50 times faster than glucose, and that glucose facilitated SLC2A9-mediated urate transport. Similarly, over expression of SLC2A9 in human embryonic kidney cells more than doubled their urate uptake. Conversely, when the researchers used a technique called RNA interference to reduce the expression of mouse SLC2A9 in mouse cells that normally makes this protein, urate transport was reduced. Researchers then looked at two genetic variations within SLC2A9 that vary between individuals (so-called single polynucleotide polymorphisms) in nearly 900 men who had had their serum urate levels and urinary urate excretion rates measured. They found that certain genetic variations at these two sites were associated with increased serum urate levels and decreased urinary urate excretion. Finally, the researchers used a statistical technique called meta-analysis to look for an association between one of the SLC2A9 gene variants and blood pressure. In two separate meta-analyses that together involved more than 20,000 participants in several studies, there was no association between this gene variant and blood pressure.
Overall, these findings indicate that SLCA9 is a high capacity urate transporter, and suggest that this protein plays an important part in controlling serum urate levels. They provide confirmation that common genetic variants in SLC2A9 affect serum urate levels to a marked degree, although they do not show exactly which genetic variant is responsible for increasing serum urate levels. They also provide important new insights into how the kidneys normally handle urate and suggest ways in which this essential process may sometimes go wrong. The findings could eventually lead to new treatments for gout and possibly for other diseases that are associated with increased serum urate levels.
Professor Mark Caulfield said: "This MRC funded study shows how a team of international researchers can find a completely unsuspected mechanism for urate handling in the kidney. Such discoveries could pave the way for new medicines."
Citation: Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ, et al. (2008) SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 5(9): e197. doi:10.1371/journal.pmed.0050197For further information contact:
At the heart of the School's mission lies world class research, the result of a focused programme of recruitment of leading research groups from the UK and abroad and a £100 million investment in state-of-the-art facilities. Research is focused on translational research, cancer, cardiology, clinical pharmacology, inflammation, infectious diseases, stem cells, dermatology, gastroenterology, haematology, diabetes, neuroscience, surgery and dentistry.
The School is nationally and internationally recognised for research in these areas, reflected in the £40 million it attracts annually in research income. Its fundamental mission, with its partner NHS Trusts, and other partner organisations such as CRUK, is to ensure that that the best possible clinical service is underpinned by the very latest developments in scientific and clinical teaching, training and research.
Alex Fernandes | EurekAlert!
Cells communicate in a dynamic code
19.02.2018 | California Institute of Technology
Studying mitosis' structure to understand the inside of cancer cells
19.02.2018 | Biophysical Society
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
19.02.2018 | Materials Sciences
19.02.2018 | Materials Sciences
19.02.2018 | Life Sciences