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.
Highlights
Interstitial cystitis/painful bladder syndrome (IC/Phosphatebuffered saline (PBS)) is a clinical syndrome characterized by chronic pelvic pain are poorly understood, and the therapeutic strategies against this disorder are still limited and unsatisfactory[3].more research is needed to clarify the pathogenesis of IC/BPSIn recent years, increasing evidence has demonstrated that bladder interstitial Cajal-like cells (ICC-LCs), whichCreative Commons license
We have found that bladder interstitial Cajal cells (ICCs)-LC hyperactivity induced by alterations in the hyperpolarization-activated cyclic nucleotide 1 (HCN1) channel are involved in cyclophosphamide (CYP)-induced cystitis[12], investigations attempting to more comprehensively elucidate the mechanisms underlying the functional role of bladder ICC-LCs in cystitis will be beneficial in developing more therapeutic strategies for cystitis-associated bladder dysfunction
To test whether the CYP-induced cystitis models were successfully established in rats, Hematoxylin and eosin (H&E) staining was primarily performed on rat bladder sections from four groups: control, CYP-4h, CYP-48h, and CYP-8d groups
Summary
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a clinical syndrome characterized by chronic pelvic pain are poorly understood, and the therapeutic strategies against this disorder are still limited and unsatisfactory[3].more research is needed to clarify the pathogenesis of IC/BPSIn recent years, increasing evidence has demonstrated that bladder interstitial Cajal-like cells (ICC-LCs), whichCreative Commons license. Interstitial cystitis/painful bladder syndrome (IC/PBS) is a clinical syndrome characterized by chronic pelvic pain are poorly understood, and the therapeutic strategies against this disorder are still limited and unsatisfactory[3]. In recent years, increasing evidence has demonstrated that bladder interstitial Cajal-like cells (ICC-LCs), which. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. To view a copy of this license, http:// creativecommons.org/licenses/by-nc-nd/4.0/
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