Role and mechanism of Roux-en-Y gastric bypass in the treatment of diabetic urinary bladder hyperactivity by reducing TRPV1 and P2X3.

Background: Diabetes mellitus (DM) is linked to an earlier onset and heightened severity of urinary complications, particularly bladder dysfunction, which profoundly impacts patient quality of life. Overactive bladder (OAB) is a common storage disorder of the lower urinary tract and is characterized by urgency, frequency, and nocturia. Several factors contribute to bladder dysfunction in diabetic individuals, including changes in urothelial signaling, detrusor morphology, and central nervous system regulation. The transient receptor potential vanilloid type 1 channel, expressed by bladder urothelial cells, is upregulated in OAB and plays a crucial role in ATP release during bladder filling. This ATP release subsequently activates purinergic receptor P2X3, further exacerbating OAB symptoms.

Aim: To clarify the mechanism of Roux-en-Y gastric bypass (RYGB) metabolic surgery to improve OAB in type 2 DM (T2DM).

Methods: The model of T2DM was induced by feeding a high-fat diet to mice for 16 weeks. After 16 weeks, sham operation and RYGB operation were performed. The related indexes of glucose metabolism were also detected to evaluate the therapeutic effect, and the recovery degree of bladder function and micturition behavior of mice was assessed by urodynamics and micturition spot analysis.

Results: Compared with the normal mice in the sham group, T2DM mice had increased urine spot count, uncontrolled urination behavior, shortened urination interval, and reduced bladder capacity. Immunohistochemistry and immunofluorescence costaining showed that Transient receptor potential vanilloid type 1 (TRPV1) and purinergic receptor P2X3 were both expressed in mouse bladder epithelial layer, and they had the same localization. In the bladder of T2DM mice, the mRNA and protein expression of TRPV1 and P2X3 were significantly increased. The ATP content in urine of T2DM mice was significantly higher than that of the sham group. After RYGB operation, the glucose metabolism index of the RYGB group was significantly improved compared with the OAB group. Comparing the results of urine spots, urodynamics, and histology, it was found that the function and morphological structure of the bladder in the RYGB group also recovered obviously. Compared with the OAB group, the expression of TRPV1 and P2X3 in the RYGB group was downregulated, and the level of inflammatory factors was significantly decreased. RYGB significantly decreased the content of ATP in urine and activated AMPK signaling.

Conclusion: RYGB downregulated the expression of TRPV1 by inhibiting inflammatory factors, thus inhibiting the enhancement of P2X3 by TRPV1. RYGB directly inhibited the activity of P2X3 by inhibiting ATP synthesis in the bladder epithelium to improve OAB.