TRPV4 agonist GSK1016790A increases mucus production and alleviates diabetic intestinal injury by activating the Ca2+/CAMKII/GSK3β pathway.

Diabetic patients often have intestinal dysfunction, such as diarrhea, constipation, abdominal pain, etc., and are accompanied by excessive inflammation. However, the underlying molecular mechanisms by which diabetes causes intestinal damage remain largely unclear. Here, we investigated the protective effect and detailed mechanism of Transient Receptor Potential vanilla protein 4 (TRPV4) agonist GSK1016790A in the treatment of diabetes-induced intestinal injury in mice. The in vivo efficacy of GSK1016790A was evaluated using a streptozotocin (STZ)-induced diabetic mouse model of intestinal injury. Jejunal and colon sections were analyzed to assess intestinal injury by hematoxylin and eosin (HE) staining, Alcian blue-periodic acid Schiff (AB-PAS) staining, and immunofluorescence. Western blotting was used to detect the changes in the expression levels of tight junction protein occludin, pro-inflammatory factor-related proteins, mucin MUC2, calmodulin-dependent protein kinase II (CAMKII) and glycogen synthase kinase 3β (GSK3β)-related protein in the intestinal tract of mice. The TRPV4 agonist GSK1016790A can significantly ameliorate intestinal mucosal structural disorder and decreased mucin secretion in diabetic mice, and downregulat the expression of pro-inflammatory factors. The underlying mechanism is to increase mucus synthesis through the mediated Ca2+/CAMKII/GSK3β pathway, thereby repairing diabetic intestinal injury. Therefore, the GSK1016790A therapy may have promising potential for the treatment of diabetic intestinal injury.