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The phosphodiesterase type 4 inhibitor roflumilast suppresses inflammation to improve diabetic bladder dysfunction rats

  • Urology - Original Paper
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Abstract

Purpose

To demonstrate that phosphodiesterase type 4 (PDE4) inhibitors could potentially treat diabetic bladder dysfunction (DBD) through modulation of the systemic inflammatory response.

Methods

In this 6-week study, 60 female Sprague–Dawley rats were divided into three groups: (i) vehicle-treated control rats; (ii) vehicle-treated streptozocin (STZ)-injected rats; and (iii) roflumilast-treated STZ-injected rats. Oral roflumilast (5 mg/kg/day) was administered during the last 4 weeks of STZ injection to induce diabetes in the test group. At 6 weeks, a urodynamic study was performed in each group. The expression of nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β in detrusor smooth muscle (DSM) was analyzed using quantitative reverse transcription-polymerase chain reaction and Western blotting.

Results

A significant decrease in bodyweight and significant increases in bladder weight and blood glucose level were observed in the diabetic rats and were not ameliorated by roflumilast treatment. Cystometry showed the increased bladder capacity, voiding volume, residual urine volume, and voiding interval in the diabetic rats and the prevention of these changes by roflumilast. These changes were accompanied by significantly enhanced expression of NF-κB, TNF-α, IL-6, and IL-1β in DSM tissue from diabetic rats. Furthermore, roflumilast attenuated the expression of inflammatory factors in DSM tissue.

Conclusions

Oral treatment with roflumilast in diabetic rats improves bladder function and inhibits the expression of inflammatory factors in DSM tissue, indicating that PDE4 is a potential therapeutic target for DBD.

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References

  1. Daneshgari F et al (2009) Diabetic bladder dysfunction: current translational knowledge. J Urol 182(6):18–26

    Google Scholar 

  2. Lin CC et al (2013) Time trend analysis of the prevalence and incidence of diagnosed type 2 diabetes among adults in Taiwan from 2000 to 2007: a population-based study. BMC Public Health 13(1):318

    Article  Google Scholar 

  3. Arrellano-Valdez F et al (2014) A comprehensive review of urologic complications in patients with diabetes. Springerplus 3(1):549

    Article  Google Scholar 

  4. Wang CC et al (2009) Diabetes-induced alternations in biomechanical properties of urinary bladder wall in rats. Urology 73(4):911–915

    Article  Google Scholar 

  5. Karoli R et al (2014) A study of bladder dysfunction in women with type 2 diabetes mellitus. Indian J Endocrinol Metab 18(4):552

    Article  Google Scholar 

  6. Ueda T, Yoshimura N, Yoshida O (1997) Diabetic cystopathy: relationship to autonomic neuropathy detected by sympathetic skin response. J Urol 157(2):580–584

    Article  CAS  Google Scholar 

  7. Staskin DR, Robinson D (2009) Oxybutynin chloride topical gel: a new formulation of an established antimuscarinic therapy for overactive bladder. Expert Opin Pharmacother 10(18):3103–3111

    Article  CAS  Google Scholar 

  8. Ren LM et al (2013) Berberine improves neurogenic contractile response of bladder detrusor muscle in streptozotocin-induced diabetic rats. J Ethnopharmacol 150(3):1128–1136

    Article  CAS  Google Scholar 

  9. Kawasaki N et al (2012) Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep 2:799

    Article  Google Scholar 

  10. Haldar S et al (2015) Inflammation and pyroptosis mediate muscle expansion in an interleukin-1beta (IL-1beta)-dependent manner. J Biol Chem 290(10):6574–6583

    Article  CAS  Google Scholar 

  11. Bouchelouche K et al (2006) Human detrusor smooth muscle cells release interleukin-6, interleukin-8, and RANTES in response to proinflammatory cytokines interleukin-1β and tumor necrosis factor-α. Urology 67(1):214–219

    Article  Google Scholar 

  12. Wang Z et al (2012) Inhibition of TNF-alpha improves the bladder dysfunction that is associated with type 2 diabetes. Diabetes 61(8):2134–2145

    Article  CAS  Google Scholar 

  13. Ndisang JF (2010) Role of heme oxygenase in inflammation, insulin-signalling, diabetes and obesity. Mediat Inflamm 2010:359732

    Google Scholar 

  14. Ding H et al (2017) Treatment of obesity-associated overactive bladder by the phosphodiesterase type-4 inhibitor roflumilast. Int Urol Nephrol 49(10):1723–1730

    Article  CAS  Google Scholar 

  15. Schafer PH et al (2016) Phosphodiesterase 4 in inflammatory diseases: effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex. Cell Signal 28(7):753–763

    Article  CAS  Google Scholar 

  16. Sturton G, Fitzgerald M (2002) Phosphodiesterase 4 inhibitors for the treatment of COPD. Chest 121(5 Suppl):192S–196S

    Article  CAS  Google Scholar 

  17. Daneshgari F, Liu G, Imrey PB (2006) Time dependent changes in diabetic cystopathy in rats include compensated and decompensated bladder function. J Urol 176(1):380–386

    Article  Google Scholar 

  18. Li N et al (2016) Partial bladder outlet obstruction is associated with decreased expression and function of the small-conductance Ca2+-activated K+ channel in guinea pig detrusor smooth muscle. Int Urol Nephrol 49(1):17–26

    PubMed  Google Scholar 

  19. Li N et al (2017) Expression and function of the small-conductance Ca2+-activated K+ channel is decreased in urinary bladder smooth muscle cells from female guinea pig with partial bladder outlet obstruction. Int Urol Nephrol 49(7):1147–1155

    Article  CAS  Google Scholar 

  20. Durden E et al (2018) The economic burden of overactive bladder (OAB) and its effects on the costs associated with other chronic, age-related comorbidities in the United States. Neurourol Urodyn. https://doi.org/10.1002/nau.23513

    Article  PubMed  Google Scholar 

  21. Wang Y et al (2011) Prevalence, risk factors, and impact on health related quality of life of overactive bladder in China. Neurourol Urodyn 30(8):1448–1455

    Article  Google Scholar 

  22. Xu D et al (2017) Prevalence of overactive bladder and its impact on quality of life in 1025 patients with type 2 diabetes in mainland China. J Diabetes Complicat 31(8):1254–1258

    Article  Google Scholar 

  23. Bansal R et al (2011) Urodynamic profile of diabetic patients with lower urinary tract symptoms: association of diabetic cystopathy with autonomic and peripheral neuropathy. Urology 77(3):699–705

    Article  Google Scholar 

  24. Oger S et al (2007) Relaxation of phasic contractile activity of human detrusor strips by cyclic nucleotide phosphodiesterase type 4 inhibition. Eur Urol 51(3):772

    Article  CAS  Google Scholar 

  25. Nirmal J et al (2014) Functional and molecular characterization of hyposensitive underactive bladder tissue and urine in streptozotocin-induced diabetic rat. PLoS ONE 9(7):e102644

    Article  Google Scholar 

  26. Yoshizawa T et al (2018) Concomitant alteration in number and affinity of P2X and muscarinic receptors are associated with bladder dysfunction in early stage of diabetic rats. Int Urol Nephrol 50(3):451–458

    Article  CAS  Google Scholar 

  27. Sakakibara R et al (2013) Neurology and the bladder: how to assess and manage neurogenic bladder dysfunction. With particular references to neural control of micturition. Brain Nerve 53(3):181–190

    Google Scholar 

  28. Liu G, Daneshgari F (2005) Alterations in neurogenically mediated contractile responses of urinary bladder in rats with diabetes. Am J Physiol Ren Physiol 288(6):F1220

    Article  CAS  Google Scholar 

  29. Mustafa S, Ismael HN (2014) Reactivity of diabetic urinary bladder to the cholinesterase inhibitor neostigmine. Urology 84(6):1549.e1–1549.e5

    Article  Google Scholar 

  30. Yang J et al (2012) The size of large adipose cells is a predictor of insulin resistance in first-degree relatives of type 2 diabetic patients. Obesity 20(5):932–938

    Article  CAS  Google Scholar 

  31. Fathollahi A, Daneshgari F, Hannamitchell AT (2015) Effect of polyuria on bladder function in diabetics versus non-diabetics: an article review. Curr Urol 8(3):119

    Article  Google Scholar 

  32. Shoelson SE, Herrero L, Naaz A (2007) Obesity, inflammation, and insulin resistance. Gastroenterology 132(6):2169–2180

    Article  CAS  Google Scholar 

  33. Murdolo G et al (2011) Inflammatory adipokines, high molecular weight adiponectin, and insulin resistance: a population-based survey in prepubertal schoolchildren. PLoS ONE 6(2):e17264

    Article  CAS  Google Scholar 

  34. Kralisch S et al (2008) Secretory products from human adipocytes impair endothelial function via nuclear factor kappaB. Atherosclerosis 196(2):523

    Article  CAS  Google Scholar 

  35. Rohla M, Weiss TW (2014) Adipose tissue, inflammation and atherosclerosis. Clin Lipidol 9(1):71–81

    Article  CAS  Google Scholar 

  36. Donath MY et al (2008) Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Diabetes Care 31(Suppl 2):S161–164

    Article  CAS  Google Scholar 

  37. Yoon J, Ryoo S (2013) Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production. Biochem Biophys Res Commun 435(3):428–433

    Article  CAS  Google Scholar 

  38. Conti M et al (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 278(8):5493–5496

    Article  CAS  Google Scholar 

  39. El-Ashmawy NE et al (2018) Roflumilast, type 4 phosphodiesterase inhibitor, attenuates inflammation in rats with ulcerative colitis via down-regulation of iNOS and elevation of cAMP. Int Immunopharmacol 56:36–42

    Article  CAS  Google Scholar 

  40. Buenestado A et al (2012) Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide. Br J Pharmacol 165(6):1877–1890

    Article  CAS  Google Scholar 

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Funding

Supported by the LNCCC LNCCC-D16-2015 grant to Ning Li; the National Science Foundation of Liaoning Province 2015020493 grant to Ning Li.

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Authors and Affiliations

  1. Department of Urology, Fourth Affiliated Hospital, China Medical University, 4 Chongshan East Road, Shenyang, Liaoning, China

    Honglin Ding, Ning Li, Yili Liu & Ping Wang

  2. Department of Urology, Affiliated Hospital, Chifeng University, 42 Wangfu Street, Chifeng, Neimeng, China

    Honglin Ding

  3. Department of General Surgery, Shenyang 242 Hospital, 3 Leshan Road, Shenyang, Liaoning, China

    Peng Zhang

Authors
  1. Honglin Ding
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  2. Peng Zhang
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  3. Ning Li
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  4. Yili Liu
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  5. Ping Wang
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Corresponding author

Correspondence to Ning Li.

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Conflict of interest

Honglin Ding, Peng Zhang, Ning Li, Yili Liu, and Ping Wang declare that they have no conflict of interests.

Ethical approval

All applicable International, National, and Institutional Guidelines for the care and use of animals were followed.

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Ding, H., Zhang, P., Li, N. et al. The phosphodiesterase type 4 inhibitor roflumilast suppresses inflammation to improve diabetic bladder dysfunction rats. Int Urol Nephrol 51, 253–260 (2019). https://doi.org/10.1007/s11255-018-2038-z

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  • DOI: https://doi.org/10.1007/s11255-018-2038-z

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