Bladder outlet obstruction causes nocturia and metabolic syndrome in mice: a 1 year long-term study.

Chiba H1, Kitta T1, Kanno Y1, Hattori T2, Higuchi M1, Ouchi M1, Togo M1, Takahashi Y1, Masafumi K1, Nakamura M1, Michishita M3, Yoshikawa S3, Shinohara N1

Research Type

Basic Science / Translational

Abstract Category

Research Methods / Techniques

Abstract 514
Bladder Wall, Microbiome and Nocturia
Scientific Podium Short Oral Session 27
Friday 6th September 2019
10:15 - 10:22
Hall G1
Animal Study Bladder Outlet Obstruction Nocturia
1.Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, 2.Department of Medhical Affairs, Asahi Kasei Pharma Corporation, 3.Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation

Hiroki Chiba



Hypothesis / aims of study
Partial bladder outlet obstruction (pBOO) in patients with benign prostatic hyperplasia (BPH) cause lower urinary tract dysfunction, such as weak urine stream, urinary frequency, urgency, and nocturia. Although animal model of pBOO with using mice is widely used to elucidate the mechanisms of BPH, long-term effects of pBOO has not been clarified sufficiently. Moreover, it has been revealed that metabolic syndrome (MetS) associate with LUTS in middle and old age. In this study, we investigate the change of voiding function and body weight of pBOO in mice for 1-year long-term period to evaluate the association LUTS and MetS.
Study design, materials and methods
Female C57/BL6 mice were used. All mice had free access to food and water, and were kept under a 12 hr light/dark cycle. The proximal urethra was tied as in the procedure for pBOO. Sham surgery was performed at the same time, and intact group was not operated. Micturition behavior was evaluated at 1, 3, 6 and 12 months after pBOO surgery. We used aVSOP (automated voided stain on paper) method, which is a precise micturition recording system for mice. Urine stains were counted and traced, ranging from 10 to 800 μl. The parameters were voided volume and time per void, total urination frequency (day time and night time) and total urine volume. We compared the parameters between 3 groups (BOO, sham, and intact mice which is not operated). Body weight was also measured in each months respectively.
The body weight of pBOO mice significantly increased compared to the other 2 groups, sham operated mice and intact mice (34.5g vs. 25.3g vs. 24.8g) at 12 months after pBOO procedure (n=7, p<0.05) (figure1). The number of the daytime micturition frequency in the pBOO group was significantly increased compared to the intact group in 12 months. Moreover, the increase of voided volume in daytime was observed compared to the intact group (1409 micro L vs. 608 micro L) (n=7, p<0.05) (figure 2), without affecting tidal voided volume in daytime.
Interpretation of results
Animal models of pBOO have been reported previously, however, long-term study is rare. To our knowledge, this is the first report of 1-year long-term observation of pBOO in mice. This study revealed that long-term pBOO lead to increase of the daytime micturition frequency, and the daytime voided volume in mice. Mice are nocturnal animals, so the daytime is the sleep phase for mice. These results may represent long-term pBOO cause nocturia and nocturnal polyuria in human patients with BPH. Long-term pBOO also lead to increase of the body weight. 
It is well known that LUTS is the one of symptoms of MetS. On the contrary, in this study, 1-year long-term pBOO induced the increase of the body weight. This mechanism has not been clarified yet. Recently, we have reported pBOO mice could disrupts circadian rhythms. The Circadian rhythms are controlled by a master circadian clock in the hypothalamus and play a major role in regulating day-to-night rhythms of feeding behavior, sleep-wake cycles, tissue metabolism, and hormonal secretions. Nocturia causes sleep disturbance, which increase the risk of metabolic diseases, such as obesity, hypertention, diabetes mellitus through multiple mechanisms, such as changes in food intake, and physical activity, oxidative stress, and increased sympathetic activity. Our hypothesis is that long-term pBOO lead to nocturia, nocturia lead to MetS, and MetS lead to further deterioration of LUTS, that is, negative spiral of LUTS and Mets.
Concluding message
The current study has found that 1-year long-term pBOO in mice lead to the daytime micturition frequency and the daytime voided volume, and increase of the body weight. Our findings could lead to the establishment of a mouse model of BPH associated with MetS, especially elderly patients. It might be useful for the development of brand new treatment for LUTS related to MetS.
Figure 1 Figure 1
Figure 2 Figure 2
  1. Denys et al, Lower Urinary Tract Symptoms and Metabolic Disorders: ICI-RS 2014, Neurourology and Urodynamics 35:278–282 (2016)
  2. Kitta et al, Benefits and limitations of animal models in partial bladder outlet obstruction for translational research, International Journal of Urology (2018) 25, 36--44
  3. Kanno et al, Bladder outlet obstruction disrupts circadian rhythms in mice, abstract 803, ICS 2017
Funding This survey was sponsored by Asahi kasei Pharma Corporation Clinical Trial No Subjects Animal Species mouse Ethics Committee Hokkaido University