Autophagy Alters Bladder Angiogenesis and Improves Bladder Hyperactivity in the Pathogenesis of Ketamine-Induced Cystitis in a Rat Model

Simple Summary Long-term ketamine abuse may increase urinary frequency, nocturia, urgency, bladder pain, dysuria, and sometimes hematuria. Evaluation of the pathophysiological mechanism of bladder voiding dysfunction in ketamine-induced cystitis (KIC) patients is a critical step for therapy. This study uses autophagy inducer (rapamycin, mTOR inhibitor) and inhibitor (wortmannin, PI3K-III inhibitor) to identify the role of autophagy in bladder angiogenesis alteration and bladder hyperactivity improvement. The present study attempts to elucidate whether autophagy alters bladder angiogenesis, decreases inflammatory response, and ameliorates bladder hyperactivity-thereby influencing bladder function in ketamine-induced cystitis (KIC). In our methodology, female Sprague-Dawley (S-D) rats were randomly divided into the control group, the ketamine group, the ketamine+rapamycin group, and the ketamine+wortmannin group. The bladder function, contractile activity of detrusor smooth muscle, distribution of autophagosome and autolysosome, total white blood cells (WBCs) and leukocyte differential counts, the expressions of autophagy-associated protein, angiogenesis markers, and signaling pathway molecules involved in KIC were tested, respectively. The data revealed that treatment with ketamine significantly results in bladder overactivity, enhanced interstitial fibrosis, impaired endothelium, induced eosinophil-mediated inflammation, swelling, and degraded mitochondria and organelles, inhibited angiogenesis, and elevated the phosphorylation of Akt. However, treatment with rapamycin caused an inhibitory effect on vascular formation, removed ketamine metabolites, decreased the eosinophil-mediated inflammation, and ameliorated bladder hyperactivity, leading to improve bladder function in KIC. Moreover, wortmannin treatment reduced basophil-mediated inflammatory response, improved bladder angiogenesis by increasing capillary density and VEGF expression, to reverse antiangiogenic effect to repair KIC. In conclusion, these findings suggested that autophagy could modulate inflammatory responses and angiogenesis, which improved bladder function in KIC.

Automated summary

Long-term ketamine abuse can lead to various bladder issues, and this study found that autophagy plays a crucial role in improving bladder function in ketamine-induced cystitis patients.