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1 f zu{ } 18 í } Çf Chinese Journal of Tissue Engineering Research February 12, 2014 Vol.18, No.7 o Œo Ù öº Ù z ˆ 1 é 1 ˆ j 1 rö 1 Í 2 È ) ( { œ ( È Þ{ Ì ) 1 Þ 2 Þ s 1 Í n Ù o Œo º²Ÿ Ù z xçéùg ŒØŒx x o Œo x Ùg 2 o Œoqö x x efâ ²efÂ qÿj ü ok uk² ùå q o ŒoÙg Ä v qé çé ŒØŒx x º i 3 x o Œo Äxv ²f Ä q Â Ù g 9 12 ý Ù Œ q s Œ {Ãv x o Œoqöm o Œo x Ùg g o Œorºu{ ùåq ÍÙg ú ºÀ z Ù Ùg Ù o Œo gè o Œoo Ù, Ùg ž «Ù 2012 òá y ÊÈr(3502Z ) Èrüz Ù o Œo ICC Â«Œˆ öº äqu{ o Œo o q öoi o ŒoÙg grºu{ ÍÙg ú rq o Œo Ù ²Ÿ Ù z 50 ù yu Ä Ù Í (n=42)xê Œƒ o Ù d (n=8) r Ï {q À ÉÌ 9 12 Ÿ Ù v ŒØŒ x Ùí o Œo x Ùíx Ù Ù g 42 ù Ù 20 ù Ø Ç o o Ùf 9 9 ù o Ù 6 ù ŒØŒ x 3 ù x 12 ù 9 ù o Ù 1 ù ŒØŒx 8 ù x (89%) o Œ o Ù Ø(0.72±0.08) ml ³ ï Â(0.63±0.05) kpa Œ Ø(2.01±0.05) ml ö ŒÈ Ø(3.47±0.41) ml/kpa d öx ± i(p <0.001) Ù ù o Øý 12 öm o Œo ŸjÇ Œ Ø}r q Ù ý n 1969 n 2006 Î Ú Ú { x î À ö Ôd þ³ { œ Þ È doi: /j.issn [ f É ú:r318 h u:b ú: (2014) ÈÍ ˆ é ˆ j rö Í. o Œo Ù öº Ù z[j].f zu { (7): Establishment of diabetic cystopathy guinea pig model and its urodynamic evaluation Luo Guang-cheng 1, He Zhi-hua 1, Luo Jian-zhen 1, Xu Yi-ming 1, Ma Hong 2 ( 1 Department of Urology, Zhongshan Hospital of Xiamen University (Teaching Hospital of Fujian Medical University), Xiamen , Fujian Province, China; 2 Department of Endocrine, Zhongshan Hospital of Xiamen University (Teaching Hospital of Fujian Medical University), Xiamen , Fujian Province, China) Abstract BACKGROUND: Diabetic cystopathy is one of the most common chronic diabetic complications. The establishment of animal models of diabetic cystopathy will provide experimental animal platform for relevant research. OBJECTIVE: To establish a guinea pig model of diabetic cystopathy and to evaluate its urodynamic characteristics. METHODS: Fifty short-hair Britain female guinea pigs were randomly divided into two groups, 42 as the experiment group and the other 8 as the control group. The experiment group was intraperitoneally injected with streptozotocin to induce diabetes. The control group received injection of blank citric acid buffered solution. Diabetic guinea pigs were detected by urinary dynamics test at 9 and 12 weeks. Diabetic guinea pigs were further assigned into diabetic cystopathy subgroup and compensated subgroup. The urodynamic parameters of three groups were compared. RESULTS AND CONCLUSION: Twenty of 42 guinea pigs were successfully induced diabetes by the injection of Luo Guang-cheng, M.D., Chief physician, Department of Urology, Zhongshan Hospital of Xiamen University (Teaching Hospital of Fujian Medical University), Xiamen , Fujian Province, China Corresponding author: Ma Hong, M.D., Chief physician, Department of Endocrine, Zhongshan Hospital of Xiamen University (Teaching Hospital of Fujian Medical University), Xiamen , Fujian Province, China Accepted: ISSN CN /R CODEN: ZLKHAH 1063

2 ˆ }. o Œo Ù öº Ù z streptozotocin. At 9 weeks after the injection, bladder function compensation was present in six diabetic guinea pigs while bladder function was decompensated in another three diabetic guinea pigs. At 12 weeks, bladder function compensation was present in one diabetic guinea pig, while another eight guinea pigs were confirmed with diabetic cystopathy (88.89%). In the diabetic cystopathy subgroup, the residual urine volume was increased (0.72±0.08) ml, maximal detrusor pressure was decreased (0.63±0.05) kpa, maximum bladder capacity was increased (2.01±0.05) ml, and bladder compliance was increased (0.34±0.04) ml/kpa. There were significant differences compared with the compensated subgroup and the control group (P < 0.001). Diabetic cystopathy occurs at 12 weeks after diabetic models are successfully established in guinea pigs, and urodynamic changes are mainly the increase of residual urine volume. Subject headings: diabetes mellitus; urinary bladder diseases; guinea pigs; models, animal; blood glucose; urination Funding: the grant by Xiamen Municipal Science and Technology Plan, No. 3502Z Luo GC, He ZH, Luo JZ, Xu YM, Ma H. Establishment of diabetic cystopathy guinea pig model and its urodynamic evaluation. Zhongguo Zuzhi Gongcheng Yanjiu. 2014;18(7): Introduction o e í t Ÿ q o öo q xf t o oi²9.7% [1] o Œo o q öoi g Ÿjg È ý g Ÿjg } ŒØŒ x [2-3] o g ŒØŒÃ v Žº m Â Ä m «Â [4-6] o Œoömqokmk Í² èé ² Žg k qèâ o rºu{ r Í y ¼É y x ¼yç } yu{ qº o rº u g u{ Í ÂÍ dº ù Ùg u{ooöm Í o Èýxö guö zqèé q º rð oùg q ± d Œƒ Ùg o ¼ ˆn± q yí oùg q [7-9] Œƒ ³²Žn β Œ ˆβ ŒØŒ Œ ü Ã ö o ~Ž p qg ³²nÄ ÙÍ³ q i ÎpÄ Ù [10-12] 1 o 2 oùg qí Œƒ qï º Ï npr Œ β Œq u ù³ 1 o ± Œƒ np ù u µéœ β ŒqØŒ ³ Œ ü oî Ê» e üž Ço k mk µ ²pt 2 oqùg o xg hgxÿq Ùg xù gxÿq Ùg oùgãso q² öm ŒØŒÃv yùg mž fùgfƒqö o Â üq np o ŒoqömÄ r Àq Â Ùgnpm u rm o Œo öoq Âr ±u x Ùg Í o Œo qk Ùg o Œo g oq öo º u g u{ g q â ºöo Í g o} [13-14] o Œo o x qÿj À Îž ù Ž Žgx ŒÎÆ ±{u x ~ Ãv Œ ØŒÃ² g Œ x ØŒ ± öm o Œog É3y [15-17] Œ³ n Ÿjg Ž Ç Œ ù² q é ÐÊ q Ä Œ y Ÿjg È Ž ÐÊ mq og y Œ³ é q Ãv g Ÿjg Â À f o Œoqö x x efâ ²efÂ qÿj ü ok uk² Œo Ÿj Œ x o Œoqº Â ùåq o ŒoÙg Ä v qé çé ŒØŒx x º i Í n Ù o Œo º²Ÿ Ù z xçéùg ŒØŒx x o Œo x Ùg ùg o Œorºu{ ùåq ÍÙg ú ² o ŒØŒÃvq 1 Materials and methods Ã dùg Í Âö Íp Ž òá Â f çãf Í ÍÙg ³ 50ù yu Ä Ù ƒ« g Í Ù«Ž Š ÍÙg ù úu SCXK( ) Í²zf Ùgq ˆ }üç k Â g y Ï ƒ «ŽSigma¹ú Laborie Ù y«žø Laborie¹ú o Ù 50ù Ù¹zÊ ²»1 ºýÃ k É d 8ù Í 42ù e Ùƒ«ž i ƒ p Ó ÍqpH mol/l À f 1064 P.O. Box 10002, Shenyang

3 ˆ }. o Œo Ù öº Ù z Í Ù Œƒ 200 mg/kgê d r Ï {q À 3 dý ÓŠ Ù ž 1 ² 4 Ã ž 16.7 mmol/lg o Ø g o u{ ž 16.7 mmol/lg «Íf 42ù Í Ù»²z r3 ù «19ù º20ù Øq o Ù² Í Ù Ù zö o Œo Ùv 20ù o Ù»²zf r2ù 9 Ã 9ù o Ù 4ù d Ù 12 ù 9ù o Ù 4ù d Ù Ùx ü 300 mg/kg Ø zì v} µ ŠÎ Éø Å Œ ef4únˆ¾é {Î ŒÈµ ºf f r² nmkr x0.25 ml/minq³ Œ ù f Ù y(laborie¹ú)ï r² ²Ÿ Œï ( ö )ö Œ ² 3f x o Œo Â Ù Œ { Ãv( >10% Œ ) g Ã ž Œ ³ ï Œ ŒÈ É xx _ ±sÿx nspss 17.0 É ±z ±nt Í P < 0.05g i 2 Results 2.1 n û Í Ù42ù ºf3ù Œƒ ý10 d¼ r rñ g Œƒ ö Ò q39ù ² 1 ºf20ù Ù Ã ž 16.7 mmol/l o Ù Øig 47.6%(20/40) 20ù o Ù ý q»fö 2 ù r rñ g o öo º18ù Í o Ù 8ù d Ù² É 2.2 n û o Ù 9 ý } Ù 9ù o Ù 6ù ŒØŒx 3ù x 12 ý }p 9ù o Ù 1ù ŒØŒx 8ù x (88.89%) x Ù Œ >10% Œ x ü d Ù 10% Œ 2.3 î e Ì ± o Œo x Ù(n=11) x Ù(n=7)ö d Ù(n=8)q Ù õ â ³ ï Œ ŒÈ x Ù Œ g(0.72±0.08) ml ³ ï g (0.64±0.05) kpa Œ g (2.01±0.05) ml ŒÈ g(4.47±0.41) ml/kpa d öx ± üõ i (P < 0.01 Ÿ1 1) x d r üõ i(p > 0.05) Ÿ 1 ox x ö d Ù Ù õ ± Table 1 Comparison of urodynamic parameters between control group, compensated group and decompensated group Ÿ d ± a P < 0.01 x ± b P < 0.01 (x _ ±s) d (n=8) x (n=7) x (n=11) (ml) ³ ï(kpa) Œ (ml) ŒÈ (ml/kpa) 0.07± ± ± ± ± ± ± ± ±0.08 ab 0.64±0.05 ab 2.01±0.05 ab 3.47±0.41 ab 3 Discussion Í x Œƒ Ù o È o Ù 12 ý Ø o Œo ³² Ù öj12 ý 88.89%q o Ùöm x o Œo v o Œ x ömq Â{ø o±gùåq x o Œo Ù Ùg ºp Ù oqž Â ef { ž 11.1 mmol/l p Ã ž 16.7 mmol/l Íf { ž g{ ~³ qž Îq Í Ùgƒ¼ ƒ Ø ri [18] ù Ù ²zf Ø gqï Ø ² Œ³ o Øi47.6% (20/42) 1 ox x ö d Ù Ù Œï Figure 1 Cystometry of detrusor pressure in control group, compensated group and decompensated group f a g d b gx c g x c x ³ ï Â ƒ Pdet Ÿx³ ï (cm H 2 O) ISSN CN /R CODEN: ZLKHAH 1065

4 ˆ }. o Œo Ù öº Ù z ri7.14%(3/42) Joseph} [19] ² Â Â gq È Ãs Íq o Ùv q ri 20ù o Ù 2ù r(10%) ÍÙg o Œoqº Ÿjf x gr Œ k f vq Â Í ¹Hagstroem} [20] q Â Œ ig >10% Œ o Œoq Ù Ÿj ² Œ ² ³ Â Œ Ø mž y}ÿj qçj s Œ ØŒ x o Œo ŒØŒ x qv [21] g ¹k ý ²é q o ~ Çj Œo [22] o Œ ÉgefÂ Œx ñ Ÿjg È} ÁÈ ý ŒØ Œ x Çj {Ãv [23] u } [24] n8 ÚÄ SD Ù ¼ 1% Œƒ o ÙqÙ g Ù²Ÿ d 8 ý Œ okéf Œ³ ok ä d ± o Ùž éî ƒ«ã± 24 h Œ Ø µr Œ ï x o Ù Œ ê Ò Ø x éî i Âƒ À ù o Ù Œ³ Ê m ù o Ù íùçj Œ³ ØŒq À é} [25] o Œƒ o Ù 2 o Ù Œ³ v Œ É o ŒØŒÃvöo Í öjnà ³ Ÿjg ³ Œƒz ž~ ŒiÂqÂÃ ŒÂŒñ ŒÂfÂ² Ã Œ{² ö Ã² 12 ² ±4 Ø Â rº ²zg fx Ã Œ ³ x ý Ž ŒØŒÃvq²z g o Ù Œ³ q ŒÂ«x Ãs Âq À Daneshgari} [26] u{ x x9 12 ef Â o Ù Œ³ xãs Âq À Œ ³ Â o Ù 912 öm ŒØŒx ý x ± oùg q ± d xg hgxÿq Ùg xùgxÿq Ùg np o Œ oqömä r Àq Â üùgçj o Œ oq Âk² Ùgnpm u rm o Œo öoq Âr u n ÙgÍ o Œo g Í ¼q ÈÙg Í o Ùöm o Œoq Â g10 [27] Œ ŒØŒqx x qçéê 1066 Ø Í Ù ŒØŒx x q üâ ² É ± v o o Ù12 ýçj Œ ØŒ x ² k t n äq Ùg h Í o [28] ² Ùg{ À Âöm ŒØŒÃv gì x Œoqöm Â ² v rð g Ù g o Œoq [16 29] Ù g Ÿjg Œ Ã² ³ Â} Çj Œ } [30] u{ o Œoq Ë Ù ä ÉÌ n Ë Ù ²Ÿ i i Ë Œ ö g o ŽùÇ j Ù ºfùŒx iâƒg n Ë Ù ù o Œ o Ù z ŒØŒ Í Ù Ÿ ö j 9 µé o Ù ŒØŒ ùx (6/9) ³ ï ö Œ Çj ä ¼ q ~u{köj [31] o Ù8 M3 ƒqm gü Ø ü Œq ØŒ ² x o ŒØŒqx n ² Íq Ù rpí 12 ý o Ù ŒØŒ² 9ùfq8ùÇj ŒØŒ x ³ ï Âƒ Œ éî ŒÈ Î ÍÙg Âvq Ù Ä Ø mž Ñ Åi Ž q n Œ x Œï Ùg q öý Íu{º i [32-33] ºp o Œoqokmk Í Åq ³ x xö q ºfg q [34-35] ³ ok ùœ g ŒÂq² º ƒ É ä Œ¼ ú~ xö } [36-39] Îž ùœ³² µ x ² Ž ä x rgöžn rg q Ø ²qx Žx ± x ~ Ã v [40-41] Œ¼x mà ü Ã xöý Îµx µ±²x mà Ãv Œo qöm º [42] µ } [43] o o Ù oðý³ Î x fx mà qÿ²ö i SD ÙÉg o ênx mà ênœ Šü n x mà Œ ²Ÿ x d ž ƒp o o Ù x mà Œ oý Œ Î x fx mà qÿ ± Å o Ø ox mà o Ù Œo qöo²zfº n o x mà ùœ Ùp o Ù Œo o Ã± ØŒ Œ qº ØŒ yv«~tx oùg ŒØŒ q¼ P.O. Box 10002, Shenyang

5 ˆ }. o Œo Ù öº Ù z ÐÊ Ãv º [44-45] pé} [45] o Ù o Œo(DCP)³ f q mà ƒmrna qqÿ² c-kitÿ² Ù o Œoqº öºöo Í x o Œo c-kitmrnaÿ² c-kit qÿ² ƒp d ö o Å Œo Ù o Œo³ f c-kitmrna c-kit qÿ²ã Žc-kit ú³ v ˆCajal Œ ŒfqØŒÃ Ž³ Ø ŒÃvöm o Œo c-kitÿ² ùœ o Œoqöo Íi i o öqx ³ öº ƒ xö Œ qøœ µõ o o Œoqokmk²z o Œoqöo Í Í d v q u [47-50] ²y qok Ígrºu{ Ço kgy o Âqu{{Â o ŒoÙg º qz Ä Çq Í q o Œo Ù g ŒØŒ x ÐÅ h ² [21 23] o ŒoÉgef g Œx Œx ñ g Œ x Çj Œx qog È ÙgÊ±ÄÌ [51] x x o Œo Äxv ²f Ä q Â Ù g9 12 ý Œ q s Œ {Ãv x o Œoqöm Í Ù x q o ŒoÙg ùg u{ o Œo} o öo ùåq ÍÙg ú Ž { «n d «h Â ý ncþ³ Î c î Æh ý ncýè þ³cý n ò À þ³cý nc dý n n þ³ dý ncþ³ d ÌrÀ{ À À í q d k «n t 2009 wethical issues in animal experimentationx üì íd Ìq r c Àc c óë Ñc Å jc îc Ê r á ò ½ é Ñd u k À í À d 4 õ h References [1] Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med. 2010;362(12): [2] Daneshgari F and Moore C. Diabetic uropathy. Semin Nephrol. 2006;26(2): [3] Golbidi S, Laher I. Bladder dysfunction in diabetes mellitus. Front Pharmacol. 2010;1:136. [4] Lin TL, Chen GD, Chen YC, et al. Aging and recurrent urinary tract infections are associated with bladder dysfunction in type 2 diabetes. Taiwan J Obstet Gynecol. 2012;51(3): [5] Gomez CS, Kanagarajah P, Gousse AE. Bladder dysfunction in patients with diabetes. Curr Urol Rep. 2011;12(6): [6] Lee WC, Wu HP, Tai TY, et al. Investigation of urodynamic characteristics and bladder sensory function in the early stages of diabetic bladder dysfunction in women with type 2 diabetes. J Urol. 2009;181(1): [7] Alimohammadi S, Hobbenaghi R, Javanbakht J, et al. Protective and antidiabetic effects of extract from Nigella sativa on blood glucose concentrations against streptozotocin (STZ)-induced diabetic in rats: an experimental study with histopathological evaluation. Diagn Pathol.2013;15(8): [8] Chaudhry ZZ, Morris DL, Moss DR, et al. Streptozotocin is equally diabetogenic whether administered to fed or fasted mice. Lab Anim. 2013;47(4): [9] hé,,,}. Œƒ Í o Ù [J].f ÍÙg,2012,12(6): [10] Li Y, Sun Y, Zhang Z, et al. Cannabinoid receptors 1 and 2 are associated with bladder dysfunction in an experimental diabetic rat model. BJU Int. 2013;112(2):E [11] Jiang YJ, Gong DX, Liu HB, et al. Ability of alpha-lipoic acid to reverse the diabetic cystopathy in a rat model. Acta Pharmacol Sin. 2008n;29(6): [12] Sasaki K, Chancellor MB, Goins WF, et al. Gene therapy using replication-defective herpes simplex virus vectors expressing nerve growth factor in a rat model of diabetic cystopathy. Diabetes. 2004;53(10): [13] Mustafa S. Effect of diabetes on the ion pumps of the bladder. Urology. 2013;81(1):211.e [14] Wang Z, Cheng Z, Cristofaro V, et al. Inhibition of TNF-α improves the bladder dysfunction that is associated with type 2 diabetes. Diabetes. 2012;61(8): [15] Bansal R, Agarwal MM, Modi M, et al. Urodynamic profile of diabetic patients with lower urinary tract symptoms: association of diabetic cystopathy with autonomic and peripheral neuropathy. Urology. 2011;77(3): [16] Li WJ, Oh SJ. Diabetic cystopathy is associated with PARP/JNK/mitochondrial apoptotic pathway-mediated bladder apoptosis. Neurourol Urodyn.2010;29(7): [17] Saito M,Wada Y,Ireda K,et al.gene expression,localization, and pharmacololgical characterization of endothelin receptors in diabetic rat bladder dome.eur J Pharmacol. 2000;387(3): [18] d,i,ii,}.sd Ù o o q ± [J]. êsçy Ž y f,2010,30(8): [19] Joseph DiMattio. Alterations in ascorbic acid transport into the lens of streptozotocin-induced diabetic rats and guinea pig. Invest Ophthalmol Vis Sci. 1992;33(10): [20] Hagstroem S, Kamperis K, Rittig S, et al. Monosymptomatic nocturnal enuresis is associated with abnormal nocturnal bladder emptying.j Urol.2004;171(6 Pt. 2): ISSN CN /R CODEN: ZLKHAH 1067

6 ˆ }. o Œo Ù öº Ù z [21] Daneshgari F, Huang X, Liu G, et al. Temporal differences in bladder dysfunction caused by diabetes, diuresis, and treated diabetes in mice. Am J Physiol Regul Integr Comp Physiol. 2006; 290(6):R [22] Kebapci N, Yenilmez A, Efe B, et al. Bladder dysfunction in type 2 diabetic patients. Neurourol Urodyn. 2007;26(6): [23] Daneshgari F, Leiter EH, Liu G, et al. Animal Models of Diabetic Uropathy. J Urol. 2009;182(6 Suppl):S8-13. [24] u, ±, ²,}. o Ù Œ ØŒq [J]. dç,2012,33(16): [25] À é, h, x,}. o Ù Œ³ q [J]. f ç,2012,12(1): [26] Daneshgari F, Liu G, Imrey PB. Time dependent changes in diabetic Cystopathy in rats include compensated and decompensated bladder function. J Urol. 2006;176(1): [27] u,iß,,}. Ù o Œ q [J].jx y,2008,13(5): [28] Lee MS,Song KD,Yang HJ, et al. Development of a type II diabetic mellitus animal model using micropig. Lab Anim Res. 2012;28(3): [29] Turner WH,Brading AF. Smooth muscle of the bladder in the normal and the diseased state: pathophysiology, diagnosis and treatment. Pharmacol Ther. 1997;75(2): [30],µÐ, Ä,}. o Œoq Ë Ù ä[j].f ç ²,2010,32(7): [31] Î É,id.2 o Œ q ƒ Íu{[J].f ç ü Œž~o,2013,11(6): [32] Sasaki K, Chancellor MB, GoinsS WF, et al. Gene therapy using replication-defective herpes simplex virus vectors expressing nerve growth factor in a rat model of diabetic cystopathy. Diabetes. 2004;53(10): [33] Kikuno N, Kawamoto K, Hirata H, et al. Nerve growth factor combined with vascular endothelial growth factor enhances regeneration of bladder acellular matrix graft in spinal cord injury-induced neurogenic rat bladder. BJU Int. 2009;103(10): [34] Ichiyanagi N, Tsujii T, Masuda H, et al. Changed responsiveness of the detrusor in rabbits with alloxan induced hyperglycemia: possible role of 5-hydroxytryptamine for diabetic bladder dysfunction. J Urol. 2002;168(1): [35] Bezuijen MW,Levendusky MC,Longhurst PA.Functional response of bladder strips from streplozotocon diabetic rats depends on bladder mass. J Uro. 2003;169(6): [36] Oberbach A, Jehmlich N, Schlichting N, et al. Molecular fingerprint of high fat diet induced urinary bladder metabolic dysfunction in a rat model. PLoS One. 2013;8(6): e [37] Kanika ND, Chang J, Tong Y, et al. Oxidative stress status accompanying diabetic bladder cystopathy results in the activation of protein degradation pathways. BJU Int. 2011; 107(10): [38] Li Y, Sun Y, Zhang Z, et al. Cannabinoid receptors 1 and 2 are associated with bladder dysfunction in an expenrimental diabetic rat model. BJU Int. 2013;112(2):E [39] Leiria LO, Mónica FZ, Carvalho FD, et al. Functional, morphological and molecular characterization of bladder dysfunction in streptozotocin-induceddiabetic mice: evidence of a role for L-type voltage-operated Ca2+ channels. Br J Pharmacol.2011;163(6): [40] Fedele D. Therapy insight: sexual and bladder dysfunction associated with diabetes mellitus. Nat Clin Pract Urol. 2005; 2(6): [41] Van Poppel H, Stessens R, Van Damme B, et al. Diabetic cystopathy: neuropathological examination of urinary bladder biopsies. Eur Urol.1998;15(1-2): [42] Brown JS, Wessells H, Chancellor MB, et al. Urologic complications of diabetes. Diabetes Care. 2005;28(1): [43] µ,q,iyh,}. x mà o Ù Œo q [J]. fé Í y,2013,30(9): [44] Apodaca G. The uroepithelium: not just a passive barrier. Traffic. 2004;5(3): [45] Apodaca G, Kiss S, Ruiz W, et al. Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol.2003;284(5):F [46] pé,,,}. Ù o Œo³ f c-kitmrna qqÿ² äö i[j].f okmk, 2010,25(2): [47] Kanika ND, Chang J, Tong Y, et al. Oxidative stress status accompanying diabetic bladder cystopathy results in the activation of protein degradation pathways. BJU Int. 2011; 107(10): [48] Johnston L, Carson C, Lyons AD, et al. Cholinergie induced Ca^2+ signaling in interstitial cells of Cajal from the guinea pig bladder. Am J Physiol Renal Physiol. 2008;294(3):R645- R655. [49] Lee WC, Wu CC, Wu HP, et al. Lower urinary tract symptoms and uroflowmetry in women with type 2 diabetes mellitus with and without bladder dysfunction. Urology. 2007;69(4): [50] Li WJ, Shin MK, Oh SJ. Poly(ADP-ribose) polymerase is involved in the development of diabetic cystopathy via regulation of nuclear factor kappa B. Urology. 2011;77(5): 1265.e1-8. [51] Rasmussen H, Rumessen JJ, Hansen A, et al. Ultrastructure of Cajal-like interstitial cells in the human detrusor. Cell Tissue Res. 2009;335(3): P.O. Box 10002, Shenyang

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