Induction of detrusor underactivity by extensive vascular endothelial damages of iliac arteries in a rat model and its pathophysiology in the genetic levels

Myong Kim, Hwan Yeul Yu, Hyein Ju, Jung Hyun Shin, Aram Kim, Jaehoon Lee, Chae Min Ryu, Hong Duck Yun, Seungun Lee, Jisun Lim, Jinbeom Heo, Dong Myung Shin, Myung Soo Choo

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7 Scopus citations

Abstract

We tried to establish a reliable detrusor underactivity (DUA) rat model and to investigate pathophysiology of chronic bladder ischemia (CBI) on voiding behavior and bladder function. Adult male rats were divided into five groups. The arterial injury (AI) groups (AI-10, AI-20, AI-30) underwent vascular endothelial damage (VED) of bilateral iliac arteries (with 10, 20, and 30 bilateral repetitions of injury, respectively) and received a 1.25% cholesterol diet. The sham group underwent sham operation and received the same diet. Controls received a regular diet. After 8 weeks, all rats underwent unanesthetized cystometrogram. Bladder tissues were processed for organ bath investigation, immunohistochemistry staining, and genome-wide gene expression analysis. Awake cystometry analysis showed that frequency of voiding contractions and micturition pressure were lower in the AI-30 group than in sham group (p < 0.01). Contractile responses to various stimuli were lower in AI-20 and AI-30 groups (both p < 0.001). In the AI-20 and AI-30 groups, atherosclerotic occlusion in the iliac arteries, tissue inflammation, fibrosis, denervation, and apoptosis of bladder muscle were prominent compared to the sham. Mechanistically, the expression of purinergic receptor P2X-1 was reduced in the AI-30 group, and the genome-wide gene expression analysis revealed that genes related to IL-17 and HIF-1 signaling pathways including INF-γ receptor-1 and C-X-C motif chemokine ligand-2 were upregulated in the CBI-induced DUA rat model. A rat model of progressive VED successfully induced DUA. Abnormal tissue inflammation, fibrosis, denervation, and bladder muscle tissue apoptosis may be involved in CBI-induced DUA pathophysiology.

Original languageEnglish
Article number16328
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2019

Bibliographical note

Funding Information:
We thank Dr. Joon Seo Lim from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this manuscript. This research was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI18C2391), by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2018R1A2B2001392), by a NRF MRC grant funded by the Korean government (MSIP) (2018R1A5A2020732), and by grants (2018–098, 2018– 609) from the ASAN Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

Publisher Copyright:
© 2019, The Author(s).

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