Researchers at the UH Center for Nuclear Receptors and Cell Signaling (CNRCS) have published a new study showing that loss of the aryl hydrocarbon receptor leads to formation of uric acid stones, inflammation and precancerous lesions in the urinary bladder. The aryl hydrocarbon receptor (AhR), also known as the TCDD receptor, is a transcription factor that regulates enzymes involved in detoxification of environmental toxins. The results were made available online January 9 by the research journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The team, led by CNRCS director Dr. Jan-Åke Gustafsson, determined that the bladder toxicity occurred without exposure to any cancer-causing agents. The researchers found that the absence of AhR results in a loss of enzymes which normally would prevent the buildup of toxins and carcinogens in the bladder. Without AhR, the cells lining the bladder are destroyed and there is an invasion of immune cells to clean up the cellular debris. According to Gustafsson and colleagues, the DNA of the dead cells is normally metabolized to uric acid but the quantities are small and uric acid is excreted. However, in the AhR knockout mice, many cells die and the system is overwhelmed by uric acid which precipitates as stones in the bladder. The presence of stones causes further inflammation which then predisposes the bladder to development of cancer.

 “Loss of AhR in humans also would be expected to lead to a severe systemic disease with elevated levels of uric acid in the circulation and in joints, a disease commonly known as gout,” says Gustafsson.

Gout is a form of rheumatic disease caused by the presence of uric acid crystals in joints and soft tissues. Currently, gout affects more than 8 million Americans. The number of gout diagnoses in the United States is expected to continue climbing due to the increase in hypertension and obesity, other diseases of significant interest to CNRCS researchers.

This is the Center’s first publication in PNAS for 2012, following an October 2011 article on the estrogen receptor β and prostate cancer. PNAS is among the most-cited multidisciplinary scientific research journals. The circulation reaches over 3,000 institutions in more than 60 countries, including more than 2,200 Academy members and more than 400 foreign associates.

Established in 2009, CNRCS is the focal point of the UH health initiative. Led by Gustafsson, a world-renowned expert in the field of nuclear receptors, CNRCS researchers are involved in many aspects of nuclear receptor research, all focused on understanding the roles of these receptors in health and disease. CNRCS researchers are working toward the goal of finding new treatments for an array of significant diseases including cancer, diabetes and metabolic syndrome and degenerative neurologic diseases. Working from the Center's world-class labs, CNRCS researchers combine interdisciplinary research and dynamic collaboration with the Texas Medical Center and industry partners.

For more details or to view the abstract, visit http://www.pnas.org/content/early/2012/01/04/1120581109.abstract.

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