Mechanisms Behind Urge to Urinate Identified

In a new collaborative study funded by the National Institutes of Health, researchers discovered that a gene called PIEZO2 may be responsible for the powerful urge to urinate that we normally feel several times a day. The results, published in Nature, suggest that the gene helps at least two different types of cells in the body sense when our bladders are full and need to be emptied. 

The PIEZO2 gene contains instructions for making proteins that are activated when cells are stretched or squeezed. In this study, the researchers found that patients who are born with a genetic deficiency in PIEZO2 have trouble sensing bladder filling while experiments in mice suggested the gene plays two critical roles in this process. It may help certain bladder cells gauge expansion while also sparking neurons to relay tension signals to the rest of the nervous system.

The scientists examined medical records, performed ultrasound scans, administered questionnaires, and conducted detailed interviews with 12 patients, 5 to 43 years of age, and their families. Initially, they found that the PIEZO2 gene was highly active in a few dorsal root ganglion (DRG) neurons that send nerve signals from the mouse bladder to the brain. Aided by an advanced, real-time imaging system, they saw that the cells lit up with activity when a mouse's bladder filled with fluid. They also found that the PIEZO2 gene was turned on in some umbrella cells which are found among the cells that line the inside of a bladder.

Next, they found that deleting the gene from the neurons and umbrella cells not only reduced the cells' responses to bladder filling but also caused the mice to have problems with urination. The mutant mice showed some signs of incontinence and urinated randomly in their cages instead of in a corner as seen with control mice. Meanwhile, mutant mouse bladders required more fluid and greater pressure than normal to trigger urination which was reminiscent of the patient reports.

They also found that deleting the gene from the two cell types had longer-lasting effects. For instance, the muscles of the mutant bladders were thicker than controls, suggesting the loss of sensation remodeled the bladder. Finally, the researchers found that deleting the PIEZO2 gene from either the umbrella cells or the DRG neurons produced similar results as deleting it from both cell types simultaneously. Eliminating the gene from either cell lengthened the time that mice would take before feeling the need to squeeze their bladders and it increased the pressure applied during each squeeze.

"Urination is essential for our health. It's one of the primary ways our bodies dispose of waste. We show how specific genes and cells may play critical roles in initiating this process," said Ardem Patapoutian, senior author of the paper. "We hope that these results provide a more detailed understanding of how urination works under healthy and disease conditions."