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 Ca2+ 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+/Ca2+ 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 [Ca2+]i and result in Ca2+ overload in bladder ICC-LCs, indicating that the Piezo1 channel and NCX1 are potential novel therapeutic targets for chronic cystitis-associated bladder hyperactivity.

• Authors: Qian Liu, Bishao Sun, Jiang Zhao, Qingqing Wang, Fan An, Xiaoyan Hu, Zhenxing Yang, Jie Xu, Mingjia Tan, Longkun Li
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 50 Issue 5 Pg. 1-16 (05 07 2018) ISSN: 2092-6413 [Electronic] United States
• PMID: 29735991 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intercellular Signaling Peptides and Proteins
• MTx4 protein, Grammostola spatulata
• Membrane Proteins
• Peptides
• Piezo1 protein, rat
• RNA, Messenger
• RNA, Small Interfering
• Sodium-Calcium Exchanger
• Spider Venoms
• sodium-calcium exchanger 1
• Cyclophosphamide

Topics

• Animals
• Chronic Disease
• Cyclophosphamide (adverse effects)
• Cystitis (chemically induced, physiopathology)
• Disease Models, Animal
• Female
• Inflammation (pathology)
• Intercellular Signaling Peptides and Proteins
• Ion Channel Gating (drug effects)
• Membrane Proteins (metabolism)
• Models, Biological
• Peptides (toxicity)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Rats, Sprague-Dawley
• Sodium-Calcium Exchanger (metabolism)
• Spider Venoms (toxicity)
• Stress, Physiological (drug effects)
• Telocytes (metabolism)
• Up-Regulation (genetics)
• Urinary Bladder (physiopathology)