Increased Piezo1 channel activity in interstitial Cajal-like cells induces bladder hyperactivity by functionally interacting with NCX1 in rats with cyclophosphamide-induced cystitis

Abstract

The Piezo1 channel is a mechanotransduction mediator, and Piezo1 abnormalities have been linked to several clinical disorders. However, the role of the Piezo1 channel in cystitis-associated bladder dysfunction has not been documented. The current study aimed to discover the functional role of this channel in regulating bladder activity during cyclophosphamide (CYP)-induced cystitis. One hundred four female rats were randomly assigned to the control, CYP-4h, CYP-48h and CYP-8d groups. CYP successfully induced acute or chronic cystitis in these rats. CYP treatment for 48h or 8d significantly increased Piezo1 channel expression in bladder interstitial Cajal-like cells (ICC-LCs), and the increase in CYP-8d rats was more prominent. In addition, 2.5 μM Grammostola spatulata mechanotoxin 4 (GsMTx4) significantly attenuated bladder hyperactivity in CYP-8d rats by inhibiting the Piezo1 channel in bladder ICC-LCs. Furthermore, by using GsMTx4 and siRNA targeting the Piezo1 channel, we demonstrated that hypotonic stress-induced Piezo1 channel activation significantly triggered Ca ²⁺ and Na ⁺ influx into bladder ICC-LCs during CYP-induced chronic cystitis. In addition, the Piezo1 channel functionally interacted with the relatively activated reverse mode of Na ⁺/Ca ²⁺ exchanger 1 (NCX1) in bladder ICC-LCs from CYP-8d rats. In conclusion, we suggest that the functional role of the Piezo1 channel in CYP-induced chronic cystitis is based on its synergistic effects with NCX1, which can significantly enhance [Ca ²⁺] _i and result in Ca ²⁺ overload in bladder ICC-LCs, indicating that the Piezo1 channel and NCX1 are potential novel therapeutic targets for chronic cystitis-associated bladder hyperactivity.

Chronic cystitis: proteins may open a channel to treatment

A protein that controls the passage of ions through cell membranes is implicated in interstitial cystitis/painful bladder syndrome (IC/PBS). This condition causes chronic pelvic pain and increased urinary frequency and urgency. Current treatment options are unsatisfactory. Researchers led by Longkun Li at the Third Military Medical University in Chongqing, China, and Mingjia Tan at the University of Michigan, Ann Arbor, USA, studied the role of this membrane channel protein, called Piezo1. Increased activity of Piezo1 was linked to bladder hyperactivity in rats with drug-induced cystitis. The research also identified a synergistic interaction between Piezo1 and a second membrane channel protein. A drug that inhibits Piezo1 activity reduced bladder hyperactivity in the rats. Drugs targeting these two proteins might help to treat the chronic cystitis of patients with IC/PBS.