| Background and Aims:Diabetic cystopathy (DCP) is a kind of chronic complication in diabetic patients. Themain pathophysiology of DCP is the decrease of bladder excitability and detrusor musclecontraction, which lead to dysuresia, increase of residual urine volum, chronic urinaryretention and overflow incontinence. DCP is the result of multi-factors, which includebladder nervous lesion, detrusor muscle dysfunction, bladder uroepithelium dysfunction,proportion changes of collagen fibers and elastic fibers in bladder wall. Some preventionand cure measures based on above-mentioned mechanisms were carried out in experimentalresearches and clinical works, but the effect was limited. It could be postulated that theremay be other factors participated in the development of DCP.The normal bladder function to store and expel urine depends on the cooperation ofnerves, detrusor smooth muscle cells and interstitial cells of Cajal (ICC). Recently, themore and more researchers found the present of bladder ICC. Bladder ICCs were closeconnection with dutrusor smooth muscle cells and nerve fibers. They may play roles in thebladder contraction as a coordinated unit. Further researches showed bladder ICC is involvein the development of bladder dysfunction, such as bladder overactivity. Our prevousstudies showed the desity of detusor ICC in diabetic rats was lower than that in normalcontrol rats. There were no documents showed whether changes of ICC play roles on thedevelopment of DCP.Tyrosine kinase receptor c-kit could be activated by its ligand stem cell factor (SCF).SCF/c-kit signals were crucial for the survival and function maintance of ICC ingastrointestinal tract. The decrease of SCF and c-kit expression and disruption of ICCnetwork were found in diabetic mice. Exogenous SCF could significantly attenuate the lossof ICC and partially recover the peristalsis of gastrointestinal tract. It is not clear thatwhether the decrease of SCF expression of detrusor muscle paticpate in the changes of detrusor ICC in the diabetic animals or patients.So we used rat model of diabetes mellitus to explore the role of the changes of detrusorICC on the development of DCP and the role of SCF on the changes of detrusor ICC indiabetic rats.Methods:In the first part, we explored the relation of the changes of detrusor ICC and bladderdysfunction in diabetic SD rats. First, the rat model of diabetes mellitus was made by asingle dose intraperitoneal injection of streptozotocin (STZ,60mg/kg). Second,urodynamics indexes and spontaneous contraction of detrusor strips were measured byintravesical manometry and ex vivo detrusor strips experiment respectively in normal anddiabetic rats. Third, the changes of distribution and numbers of detrusor ICC were observedby c-kit immunofluorescence staining of detrusor tissue sheets in diabetic rats.In the second part, the roles of SCF on the changes of detrusor ICC were studied indiabetic rats. First, the levels of c-kit and SCF in detrusor tissues were measured byRT-PCR and Western Blot in diabetic rats. Second, the changes of c-kit and SCFexpression and the number of detrusor ICC were measured in diabetic rats followingadministration of exogenous SCF.In the third part, the roles of the loss of detrusor ICC on the development of DCP werefurther confirmed. The loss of detrusor ICC was attenuated by administration of exogenousSCF. Then the urodynamics indexes and spontaneous contraction of detrusor strips weremeasured by intravesical manometry and ex vivo detrusor strips experiment respectively.Main results:1. The rat model of diabetes mellitus was successfully made by a single doseintraperitoneal injection of streptozotocin (STZ,60mg/kg). The blood glucoseconcentration increased significantly at3days after STZ injection. The blood glucoseconcentration of each rat was higher than16.7mmol/L and still be high level at two weekslater.2. Compared with normal control rats, the residual urine volum, maximum bladdercapacity and bladder compliance increased significantly in diabetic rats, while themaximum intravesical pressure decreased; the amplitude and frequence of spontaneouscontraction of detrusor strips decreased significantly in diabetic rats; the detrusor ICC network of diabetic rats were disrupted severely, and the number of detrusor ICC decreaseddramatically.3. Expression of mSCF and sSCF mRNA were found in detrusor muscle tissues in ratsand the mRNA level of sSCF was obviously higher than that of mSCF. The mRNA level ofmSCF, sSCF and c-kit and the protein level of SCF and c-kit decreased significantly indetrusor muscle tissues in diabetic rats. The protein level of SCF in detrusor muscle tissuesincreased following administration of exogenous SCF in diabetic rats, while the mRNAlevel of SCF didn't change. The mRNA and protein level of c-kit and the number ofdetrusor ICC also increased significantly.4. Exogenous SCF was used to attenuate the loss of detrusor ICC in diabetic rats. Theblood glucose level and body weight didn't change as the increased of ICC. The amplitudeof spontaneous contraction of detrusor strips increased significantly, while the frequence ofthat didn't change. Urodynamics indexes including bladder compliance, maximum bladdercapacity and residual urine volum, decreased significantly along with attenuation of the lossof detrusor ICC, while the maximum intravesical pressure wasn't improved.Conclusions:1. Detrusor ICC number and SCF expression decreased significantly in the diabeticrats. Exogenous SCF could attenuate the loss of detrusor ICC. The decrease of SCF indetrusor muscle tissues contribute to the loss of detrusor ICC in diabetic rats.2. Increase of residual urine volume, maximum bladder capacity and bladdercompliance, decrease of maximum intravesical pressure, decrease of amplitude andfrequency of spontaneous contraction of detrusor strips were along with the loss of detrusorICC in diabetic rats. Exogenous SCF could increase the amplitude of spontaneouscontraction of detrusor strips and decrease residual urine volume, maximum bladdercapacity, bladder compliance by attenuation of the loss of detrusor ICC. The loss of thedetrusor ICC was involved in the development of DCP.
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