Evaluation of urinary bladder fibrogenesis in a mouse model of long-term ketamine injection

Abstract

Long-term ketamine abuse has been shown to affect the lower urinary tract and result in interstitial cystitis-like syndrome. However, the causative mechanism of ketamine-induced dysfunction remains unclear. The present study aimed to investigate the physiological, histological and molecular changes on ketamine-associated cystitis (KC) in a mouse model. Both male and female Balb/c mice were separately distributed into the control group (normal saline) and ketamine group, which received ketamine hydrochloride (100 mg/kg/day) daily by intraperitoneal injection for a total period of 20 weeks. In each group, the urine was analyzed by gas chromatography-mass spectrometry to measure the concentration of ketamine and its metabolites. Urinary frequency and urine volume were examined to investigate the urinary voiding functions. Mice bladders were excised for cDNA microarray and hematoxylin and eosin (HE) staining. The ketamine and metabolites were detected only in ketamine-treated mice urine. The voiding interval was reduced in the male mice group after 20 week ketamine administration. Additionally, the result of cDNA array analysis revealed a number of gene expression levels involved in chronic wound healing response and collagen accumulation, which were closely associated with fibrosis progression in the connective tissue. In HE staining of the bladder tissue, the ketamine-injected mice exhibited prominently denser blood vessel distribution in the submucosal layer. Based on the evidence in the present study, a mechanism that delineates fibrosis formation of urinary bladder induced by the pathogenesis of ketamine abuse can be constructed.

Gene expression and DNA methylation regulation of arsenic in mouse bladder tissues and in human urothelial cells

“…Therefore, it may be assumed that these differences are also present between rodents and humans. In a similar study, it was revealed that 25 mg/kg of ketamine induced rat bladder inflammation and cyclooxygenase-2 expression (50), whereas 100 mg/kg of ketamine did not cause significant inflammation in mouse bladder tissues (51). In the present study, we provide additional evidence that the gene regulation of CBS, ADORA1 and WIF1 was different between mouse bladder tissues and human urothelial cells.…”

<em>Aldh2</em> gene reduces oxidative stress in the bladder by regulating the NF‑&kappa;B pathway in a mouse model of ketamine‑induced cystitis

“…Numerous animal studies have demontrated that long-term ketamine treatment can lead to bladder fibrosis, which is an important cause of bladder abnormalities, including decreased capacity, lower compliance and impaired detrusor function ( 41 , 42 ). Song et al ( 41 ) demonstrated that the inflammatory mediators in KIC increased the expression of collagen type-I (COL-I) and α-SMA, which leads to thickening of the bladder basement membrane.…”

“…Song et al ( 41 ) demonstrated that the inflammatory mediators in KIC increased the expression of collagen type-I (COL-I) and α-SMA, which leads to thickening of the bladder basement membrane. Furthermore, Shen et al ( 42 ) conducted whole genome analysis and reported that the expression of fibrotic genes, including fibronectin, TGF-β1 and COL-I, were upregulated in bladder tissues with KIC. This enriched expression was considered to be a sensitive marker of active fibrosis development.…”

Effects of a new β3‐adrenoceptor agonist, vibegron, on neurogenic bladder dysfunction and remodeling in mice with spinal cord injury

“…Two micrograms of RNA were reverse‐transcribed to complementary DNA, using the ThermoScript reverse transcription polymerase chain reaction (RT‐PCR) System (Invitrogen, Grand Island, NY). The expression of fibrosis markers including collagen type 1, 10 collagen type 3, 10 transforming growth factor‐β 1 (TGF‐β1), and fibroblast growth factor 2 (FGF 2), 11 and ischemia markers including hypoxia‐inducible factor‐1 α (HIF‐1α) 12 and vascular endothelial growth factor A (VEGF A) 12 was quantified using CFX Maestro Real‐Time PCR Instruments (BIO‐RAD Laboratories, Inc, Hercules, CA) in a 25‐µL volume, using SYBRGreen PCR Master Mix (QIAGEN, Valencia, CA). Relative gene expression was normalized with the expression of β‐actin.…”