The Relationship Between ICCs And Bladder Dysfunction In Bladder Of Diabetic Cystopathy Rats And The Role Of ICCs In Diabetic Cystopathy

Background and objectiveThe aim of this study is to explore the density distribution of interstitial cells of Cajal ( ICCs) in the bladder of rats with diabetes mellitus (DM) and its effects on the excitability of the detrusor and the bladder function. As known to all,diabetes mellitus is a common disease, with the improvement in the quality of people's lives, the incidence of which also showing increasing trend year by year in China. Diabetic bladder dysfunction (DBD), also known as Diabetic cystopathy (DCP), is a common urinary tract complication in diabetes patients. The incidence of this complication can account for 40% ~ 90% in patients with DM. Diabetic cystopathy is often concealed in its early onset, developing without symptoms, so clinicians and patients with diabetes always neglect it until late stage. The patients often show the diabetic bladder dysfunction in late stage. Due to the disappearance of bladder detrusor contractility, the patients appear dysuria, residual urine increasing, chronic urinary retention and overflow incontinence, etc in late stage. These symptoms seriously affect the quality of life and health conditions of patients. Early prevention and treatment of diabetic bladder dysfunction is the common job in Urology, Endocrinology, Neurology and gerontology.However, the etiology of bladder dysfunction in diabetes has not yet been fully understood. Its incidence has nothing to do with sex and age, besides, currently scholars in this field generally agreed that it relates to the duration of diabetes or the incidence and degree of peripheral neuropathy, or many other factors. It's well known that the main mechanism of bladder dysfunction is diabetic peripheral neuropathy. However, accordingly, the effect of nerve receptor agonist is not satisfactory for bladder dysfunction, which indicating the existence of some other the pathogenic mechanism besides nerve injury. Clinically, nerve damage is unlikely to reverse, so it is particularly important to explore the correct mechanism, which can lead therapy of diabetic bladder dysfunction.Cajal interstitial cells (ICCs) act as the pacemaker of smooth muscle activation in gastrointestinal tract. They play roles in producing gastrointestinal basic electrical rhythm(BER), transmitting electrical signal and mediating the signal between intestinal nerve and smooth muscle. It's important for ICCs to maintain normal structure, distribution and function to regulate gastrointestinal motility. The abnormal distribution of ICCs and the destroy of cellular network may related with gastrointestinal motility disorders, such as Hirschsprung's disease and chronic transmitting constipation. Previous studies at home and abroad have found: there are ICCs in many organs, such as renal pelvis, ureter and bladder, using phase contrast microscope, immunohistochemical staining and electron microscopy. However, the role of ICCs in urinary tract is still unknown. Studies demonstrated that ICCs in urinary tract presented spontaneous excitability. Some further studies indicated that the number of ICCs in the pyeloureteral junction decreased in patients with congenital pyeloureteral junction obstruction, and the number of ICCs in bladder decreased in patients with megacystis-microcolon intestinal hypoperistalsis syndrome. The mumber of ICCs increased in overactivity bladder with the bladder outlet obstruction. Previously we found that ICCs increased significantly in bladder with BOO in rats model, which indicated ICCs may contribute to bladder activity. Realization of advanced diabetic bladder excitatory and contractile function decreased significantly, are ICCs also involved in its pathogenesis?C-kit receptors, which determined by a proto-oncogene kit encoding tyrosine kinase receptors, can be expressed in ICC cells, mast cells and hematopoietic cells and other cells. Only ICCs and mast cells in the bladder cells can express c-kit receptor. It is easy for us to differentiate mast cells from ICCs by its rounded shape. We can identify ICCs in bladder easily by marking with c-kit-specific monoclonal antibody.In this study,we used immunohistochemistry, bladder urodynamic testing, muscle excitability and contractility of measurement, laser scanning confocal techniques, and so on. Through comparing the morphology characteristics and the distribution density of ICCs in diabetic rats and normal control rats bladders, as well as the changes of bladder excitability and contractility, preliminarily explore the relationship between ICCs and bladder dysfunction in bladder of diabetic cystopathy rats and the role of ICCs in diabetic cystopathy. The results may help to further clarify the mechanism of bladder dysfunction in DM, and provide a new target point for clinic treatment.MethodsAnimal models of DM were made in SD rats by intraperitoneal injection of streptozotocin and identified by fast blood glucose over 16.7mmol/L. There were 2 groups of rats,DM group(n=20)and age-matched group(n=10). The residual urine volume,the maximum bladder capacity, the maximum bladder pressure and bladder compliance were examined by cystometry and compared between DM group and control group 12 weeks later. The changes of detrusor excitability and contractility compliance were examined by the detrusor strip study in vitro. The ICCs in detrusor tissue pieces were detected by immunofluorescent staining. At last,these parameters got from both groups were anlyzed with t text.ResultsWe successfully made animal models of DM were made in SD rats. The diabetic rats exhibited polydipsia, polyphagia, polyuria, weight loss symptoms. In diabetic rats, the residual urine volume(P<0.01),the maximum bladder capacity (P<0.01) and compliance (P<0.01) were increased, however the maximum bladder pressure (P<0.05) was decreased compared to that in the controls. The contraction frequency (P<0.05) and amplitude of strips of diabetic rat bladder were decreased. There were less ICCs in the bladder detrusor of rats with DMthan that in controls(P<0.05). Conclusion1. Animal models of DM can be made in SD rats by intraperitoneal injection of streptozotocin.2. The excitability and contractility of bladder significantly decrease or disappear in DM bladder of rats, which may be associated with the muscle-derived factors.3. ICCs in DM bladder of rats with are significantly decreased, which may play an important role in the changes of the excitability of detrusor and bladder function in DM rats.