October 27, 2020

How your body senses the urge to urinate

At a Glance

  • Researchers discovered a gene that may be responsible for the powerful urge to urinate that we normally feel many times throughout the day.
  • These findings expand the growing list of newly discovered senses under the gene’s control.
Microscope image of mouse bladder Researchers discovered a protein that may help us sense when our bladders are full. Above is an example of a mouse bladder used in the study. Patapoutian lab, Scripps Researcher Institute

How often you need to urinate depends on how quickly your kidneys produce the urine that fills the bladder. It also depends on how much urine your bladder can comfortably hold. Over time, your bladder fills up and expands like a balloon, putting tension on the bladder muscles. At a certain point, the body senses that it is reaching a limit, which triggers the urge to urinate.

But how your body senses a full bladder isn’t known. Certain proteins can be activated by cells being stretched or squeezed. One gene, called PIEZO2, holds the instructions to make such proteins. PIEZO2 has been shown to play a role in sensing mechanical stimulation, including touch, vibration, pain, and proprioception (the awareness of one’s body in space).

To investigate whether PIEZO2 also helps the body sense a full bladder, a research team led by Dr. Ardem Patapoutian at the Scripps Research Institute, Dr. Alex Chesler at NIH’s National Center for Complementary and Integrative Health (NCCIH), and Dr. Carsten Bönnemann at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) studied how mutations in PIEZO2 affect people and mice. Results were published on October 14, 2020 in Nature.

The researchers examined 12 patients at the NIH Clinical Center, ages 5 to 43 years, who were born with inactivating mutations in their PIEZO2 genes. The team reviewed medical records, performed ultrasound scans, administered questionnaires, and conducted detailed interviews with the patients and their families.

Most patients reported problems with urination. Nearly all could go an entire day without feeling the urge to urinate. Most urinated less than the normal five to six times per day. Seven said they found it difficult to urinate. They either had to wait for it to happen or needed to press their lower abdomen for it to start.

The researchers also studied PIEZO2 in the cells involved in bladder control in mice: dorsal root ganglion (DRG) neurons, which send nerve signals from the mouse bladder to the brain, and “umbrella” cells that line the inside of the bladder.

Genetically removing PIEZO2 from either the neurons or the umbrella cells reduced the cells’ response to the bladder filling. It also caused the mice to have urination problems. Mice with the genetically altered cells required more fluid and greater pressure in the bladder to trigger urination. This phenomenon was similar to the patient reports. Mice with the mutated gene also had thicker bladder muscles than the controls, suggesting that the loss of sensation altered the bladder over time.

“Our results show how the PIEZO2 gene tightly coordinates urination,” Chesler says. “This is a major advance in our understanding of interoception—or the sense of what’s going inside our bodies.”

“Urination is essential for our health. It’s one of the primary ways our bodies dispose of waste,” Patapoutian adds. “We hope that these results provide a more detailed understanding of how urination works under healthy and disease conditions.”

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References: PIEZO2 in sensory neurons and urothelial cells coordinates urination. Marshall KL, Saade D, Ghitani N, Coombs AM, Szczot M, Keller J, Ogata T, Daou I, Stowers LT, Bönnemann CG, Chesler AT, Patapoutian A. Nature. 2020 Oct 14. doi: 10.1038/s41586-020-2830-7. Online ahead of print. PMID: 33057202.

Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and National Center for Complementary and Integrative Health (NCCIH); Howard Hughes Medical Institute.