KCNN4 Potassium Channel Might Help in IBD Diagnosis, Treatment

KCNN4 Potassium Channel Might Help in IBD Diagnosis, Treatment

KCNN4 potassium channel might be a new diagnostic marker and therapeutic target in inflammatory bowel disease (IBD), a study suggests.

The study, “KCNN4 Expression Is Elevated in Inflammatory Bowel Disease:  This Might Be a Novel Marker and Therapeutic Option Targeting Potassium Channels,” was published in The Journal of Gastrointestinal and Liver Diseases.

The potassium channel KCNN4 is associated with many inflammatory diseases. That is due to its involvement in ion transport and intestinal epithelial restitution — a protective mechanism in which epithelial cells migrate and spread rapidly in response to a wound or injury.

In IBD, a defective epithelial barrier — the lining of the intestines — can lead to characteristic disease symptoms such as diarrhea and intestinal ulcers.

Seeking to better understand the role of KCNN4, researchers at the University Hospital Regensburg, in Germany, compared surgical samples from patients with IBD — specifically, ulcerative colitis or Crohn’s disease — those with non-IBD intestinal inflammatory conditions such as diverticulitis, and controls without inflammation. In this case, the controls were patients with colorectal cancer.

The goal was to determine if KCNN4 could potentially be involved in intestinal restitution in IBD.

To find out, the team measured mRNA, or messenger RNA, the molecule generated from DNA and used as the template for protein production, as well as protein levels of both KCNN4 and a control potassium channel called KCNQ1. In addition, the scientists investigated the role of KCNN4 in epithelial barrier integrity in the lab (in vitro).

Data were analyzed using appropriate statistical models.

The study included 60 patients (51.7% female), with a mean age of 47.9 at the time of surgical intervention. Among them were 28 people (46.7%) with Crohn’s disease, 14 with ulcerative colitis (23.3%), 10 with colorectal cancer (16.7%), and eight with diverticulitis (13.3%).

KCNN4 mRNA levels were significantly increased in the individuals with ulcerative colitis, with a mean increase of 658.2%, and in those with Crohn’s disease, who had a mean increase of 415.6%. However, the levels were not increased (0%) in patients with colorectal cancer. The levels of KCNQ1 mRNA were comparable in all groups.

According to the scientists, these findings suggest an involvement of KCNN4 in IBD development and disease course.

Regarding KCNN4 protein levels, these also were increased in intestinal epithelial cells from patients with intestinal inflammation compared with controls without inflammation. Specifically, those with ulcerative colitis, Crohn’s disease, and diverticulitis had a mean increase of 63.8%. Meanwhile, the patients without inflammation — those with colorectal cancer – had a 0% increase. KCNQ1 protein levels were similar in all groups.

The team then used interferon-gamma (IFN-gamma) to assess epithelial cell permeability. Of note, IFN-gamma is a pro-inflammatory factor that can cause epithelial damage leading to a leaky mucosal barrier.

These results showed that 48 hours of treatment with IFN-gamma led to an increase in epithelial cell permeability — with a mean increase of 24.1% — mimicking inflammation as in intestinal epithelial cells from IBD patients.

In turn, treatment of these cells with pharmacological KCNN4 channel openers, called SKA-31 and 1-EBIO, significantly reduced cell permeability, with a mean decrease of 17.3% with SKA-31 and 36.7% with 1-EBIO. In both cases, the treatment ultimately restored epithelial barrier integrity.

Pharmacological inhibition of KCNN4 with TRAM-34 and clotrimazole revealed no change in cell permeability.

“Our data underline the important role of KCNN4 as a therapeutic target to stabilize epithelial barrier integrity in intestinal inflammation. In contrast, pharmacological inhibition of this [potassium] channel revealed no change of the permeability of the epithelial monolayer,” the researchers wrote.

Based on the results, the team concluded that the data “demonstrate elevated KCNN4 both at mRNA and protein level in IEC [intestinal epithelial cells] specifically from patients with IBD.”

These findings may be of therapeutic consequence, the scientists said.

“We show that pharmacological KCNN4 openers stabilize the epithelial barrier. Thus, KCNN4 might be a novel target to diagnose and treat IBD,” they concluded.