Decreased hyperpolarization-activated cyclic nucleotide-gated channels are involved in bladder dysfunction associated with spinal cord injury

Liu,Qian; Wu,Chao; Huang,Shengquan; Wu,Qingjian; Zhou,Tao; Liu,Xiaobing; Liu,Xin; Hu,Xiaoyan; Li,Longkun

doi:10.3892/ijmm.2018.3489

Decreased hyperpolarization-activated cyclic nucleotide-gated channels are involved in bladder dysfunction associated with spinal cord injury

Authors:
- Qian Liu
- Chao Wu
- Shengquan Huang
- Qingjian Wu
- Tao Zhou
- Xiaobing Liu
- Xin Liu
- Xiaoyan Hu
- Longkun Li
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Affiliations: Department of Urology, The Second Affiliated Hospital, The Third Military Medical University, Chongqing 400037, P.R. China
Published online on: February 13, 2018 https://doi.org/10.3892/ijmm.2018.3489
Pages: 2609-2618
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Spinal cord injury (SCI) leads to bereft voluntary control of bladder, but the possible role of spontaneous excited system in bladder of SCI patients is poorly understood. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are deemed to regulate the spontaneous contraction of bladder, our study explored the functional role of HCN channels in SCI induced neurogenic bladder. Sixty female Sprague-Dawley rats were randomized into control, sham and SCI groups. Rat models subjected to SCI at S2 levels were successfully established and were assessed using hematoxylin and eosin staining and cystometry. In SCI rats, the mRNA and protein expression levels of HCN channels and the Ih density were significantly reduced, and expression levels of several bladder HCN1 channel regulatory proteins were also significantly changed. The effects of 50 µM forskolin and 50 µM 8-bromoadenosine 3',5'-cyclic monophosphate on [Ca2+]i of isolated bladder interstitial cells of Cajal-like cells were significantly decreased in SCI rats. The spontaneous contractions in detrusor strips from SCI rats were significantly weakened. Furthermore, detrusor strips from SCI rats exhibited decreased tolerance to two doses of ZD7288 (10 and 50 µM). Taken together, our results indicate that the decreased bladder HCN channel expression and function induced by altered regulatory proteins are involved in the pathological process of SCI induced neurogenic bladder, which present HCN channels as valid therapeutic targets for treating this disease.

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1	Thuret S, Moon LD and Gage FH: Therapeutic interventions after spinal cord injury. Nat Rev Neurosci. 7:628–643. 2006. View Article : Google Scholar : PubMed/NCBI
2	Kim JH, Shim SR, Doo SW, Yang WJ, Yoo BW, Kim JM, Ko YM, Song ES, Lim IS, Lee HJ, et al: Bladder recovery by stem cell based cell therapy in the bladder dysfunction induced by spinal cord injury: systematic review and meta-analysis. PLoS One. 10:e01134912015. View Article : Google Scholar : PubMed/NCBI
3	Ku JH: The management of neurogenic bladder and quality of life in spinal cord injury. BJU Int. 98:739–745. 2006. View Article : Google Scholar : PubMed/NCBI
4	Cetinel B, Onal B, Can G, Talat Z, Erhan B and Gunduz B: Risk factors predicting upper urinary tract deterioration in patients with spinal cord injury: a retrospective study. Neurourol Urodyn. 36:653–658. 2017. View Article : Google Scholar
5	Harris CJ and Lemack GE: Neurourologic dysfunction: evaluation, surveillance and therapy. Curr Opin Urol. 26:290–294. 2016. View Article : Google Scholar : PubMed/NCBI
6	Zhang T, Liu H, Liu Z and Wang L: Acupuncture for neurogenic bladder due to spinal cord injury: a systematic review protocol. BMJ Open. 4:e0062492014. View Article : Google Scholar : PubMed/NCBI
7	Gfroerer S and Rolle U: Interstitial cells of Cajal in the normal human gut and in Hirschsprung disease. Pediatr Surg Int. 29:889–897. 2013. View Article : Google Scholar : PubMed/NCBI
8	Sanders KM, Ward SM and Koh SD: Interstitial cells: regulators of smooth muscle function. Physiol Rev. 94:859–907. 2014. View Article : Google Scholar : PubMed/NCBI
9	McCloskey KD: Interstitial cells in the urinary bladder - localization and function. Neurourol Urodyn. 29:82–87. 2010. View Article : Google Scholar
10	McCloskey KD: Bladder interstitial cells: an updated review of current knowledge. Acta Physiol (Oxf). 207:7–15. 2013. View Article : Google Scholar
11	Deng J, Zhang Y, Wang L, Zhao J, Song B and Li L: The effects of Glivec on the urinary bladder excitation of rats with suprasacral or sacral spinal cord transection. J Surg Res. 183:598–605. 2013. View Article : Google Scholar : PubMed/NCBI
12	Yang Q, Kuzyk P, Antonov I, Bostwick CJ, Kohn AB, Moroz LL and Hawkins RD: Hyperpolarization-activated, cyclic nucleotide-gated cation channels in Aplysia: contribution to classical conditioning. Proc Natl Acad Sci USA. 112:16030–16035. 2015. View Article : Google Scholar : PubMed/NCBI
13	He P, Deng J, Zhong X, Zhou Z, Song B and Li L: Identification of a hyperpolarization-activated cyclic nucleotide-gated channel and its subtypes in the urinary bladder of the rat. Urology. 79:1411.e7–1411.e13. 2012. View Article : Google Scholar
14	He C, Chen F, Li B and Hu Z: Neurophysiology of HCN channels: from cellular functions to multiple regulations. Prog Neurobiol. 112:1–23. 2014. View Article : Google Scholar
15	Sartiani L, Romanelli MN, Mugelli A and Cerbai E: Updates on HCN channels in the heart: function, dysfunction and pharmacology. Curr Drug Targets. 16:868–876. 2015. View Article : Google Scholar : PubMed/NCBI
16	O'Donnell AM, Coyle D and Puri P: Decreased expression of hyperpolarisation-activated cyclic nucleotide-gated channel 3 in Hirschsprung's disease. World J Gastroenterol. 21:5635–5640. 2015. View Article : Google Scholar : PubMed/NCBI
17	Deng T, Zhang Q, Wang Q, Zhong X and Li L: Changes in hyperpolarization-activated cyclic nucleotide-gated channel expression and activity in bladder interstitial cells of Cajal from rats with detrusor overactivity. Int Urogynecol J Pelvic Floor Dysfunct. 26:1139–1145. 2015. View Article : Google Scholar
18	Lucin KM, Sanders VM, Jones TB, Malarkey WB and Popovich PG: Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Exp Neurol. 207:75–84. 2007. View Article : Google Scholar : PubMed/NCBI
19	Fischer AH, Jacobson KA, Rose J and Zeller R: Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc. pdb.prot4986. 2008. View Article : Google Scholar
20	Andersson KE, Soler R and Füllhase C: Rodent models for urodynamic investigation. Neurourol Urodyn. 30:636–646. 2011. View Article : Google Scholar : PubMed/NCBI
21	Goldmark E, Niver B and Ginsberg DA: Neurogenic bladder: from diagnosis to management. Curr Urol Rep. 15:4482014. View Article : Google Scholar : PubMed/NCBI
22	Bender RA and Baram TZ: Hyperpolarization activated cyclic-nucleotide gated (HCN) channels in developing neuronal networks. Prog Neurobiol. 86:129–140. 2008. View Article : Google Scholar : PubMed/NCBI
23	Santoro B, Piskorowski RA, Pian P, Hu L, Liu H and Siegelbaum SA: TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron. 62:802–813. 2009. View Article : Google Scholar : PubMed/NCBI
24	Gravante B, Barbuti A, Milanesi R, Zappi I, Viscomi C and DiFrancesco D: Interaction of the pacemaker channel HCN1 with filamin A. J Biol Chem. 279:43847–43853. 2004. View Article : Google Scholar : PubMed/NCBI
25	Wilkars W, Wollberg J, Mohr E, Han M, Chetkovich DM, Bähring R and Bender RA: Nedd4-2 regulates surface expression and may affect N-glycosylation of hyperpolarization-activated cyclic nucleotide-gated (HCN)-1 channels. FASEB J. 28:2177–2190. 2014. View Article : Google Scholar : PubMed/NCBI
26	Biel M, Wahl-Schott C, Michalakis S and Zong X: Hyper-polarization-activated cation channels: from genes to function. Physiol Rev. 89:847–885. 2009. View Article : Google Scholar : PubMed/NCBI
27	Robinson RB and Siegelbaum SA: Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol. 65:453–480. 2003. View Article : Google Scholar
28	Benarroch EE: HCN channels: function and clinical implications. Neurology. 80:304–310. 2013. View Article : Google Scholar : PubMed/NCBI
29	Shahi PK, Choi S, Zuo DC, Kim MY, Park CG, Kim YD, Lee J, Park KJ, So I and Jun JY: The possible roles of hyper-polarization-activated cyclic nucleotide channels in regulating pacemaker activity in colonic interstitial cells of Cajal. J Gastroenterol. 49:1001–1010. 2014. View Article : Google Scholar
30	Wu Y, Shi C, Deng J, Zhang X, Song B and Li L: Expression and function of muscarinic subtype receptors in bladder interstitial cells of cajal in rats. Urol J. 11:1642–1647. 2014.PubMed/NCBI
31	Kubota Y, Biers SM, Kohri K and Brading AF: Effects of imatinib mesylate (Glivec) as a c-kit tyrosine kinase inhibitor in the guinea-pig urinary bladder. Neurourol Urodyn. 25:205–210. 2006. View Article : Google Scholar : PubMed/NCBI
32	Postea O and Biel M: Exploring HCN channels as novel drug targets. Nat Rev Drug Discov. 10:903–914. 2011.PubMed/NCBI
33	Riccioni G, Vitulano N and D'Orazio N: Ivabradine: beyond heart rate control. Adv Ther. 26:12–24. 2009. View Article : Google Scholar : PubMed/NCBI