Abstract
ObjectiveTo explore the role of HCN channels in ureteral peristaltic dysfunction by comparing the changes in HCN channel levels between normal and tuberculous ureters.MethodsA total of 32 specimens of human upper ureters were collected by nephrectomy from patients with renal tumor (control group, n = 16) or from patients with renal tuberculosis (experimental group, n = 16); the two groups did not receive radiotherapy, chemotherapy, immunotherapy, or any other special treatment before the surgical procedure. An experimental study on smooth muscle strips of human upper ureters showed variation in contraction amplitude and frequency after adding ZD7288, a specific blocker of HCN channels. The expression of HCN channels in the ureter was confirmed by Western blot (WB) and by confocal analysis of double immunostaining for c-kit and HCN channel proteins.ResultsBefore the addition of ZD7288, the experimental and control groups showed significant differences in the frequency and amplitude of the spontaneous contraction of isolated ureteral smooth muscle strips. After ZD7288 was added, the frequency and amplitude of the contractions of the ureteral smooth muscle strips were significantly lower in both groups. The differences observed before and after ZD7288 treatment in each group were significant (P < 0.001), and the difference in contraction amplitude observed between the two groups before ZD7288 was also significantly different (P < 0.001). By using WB technology, we showed that the expression of HCN channels was present in normal human ureters, with the expression of HCN4 and HCN1 being the highest; the expression of HCN4 and HCN1 in the control and experimental groups were both statistically significant (P < 0.001). HCN4 and HCN1 were expressed in the mucosal and smooth muscle layers of human control ureters and tuberculous ureters, as revealed by a confocal analysis of double immunostaining for c-kit and HCNs proteins; there were significant differences between the two groups (P < 0.001).ConclusionFour HCN channels are expressed in the ureter, mainly HCN4 and HCN1, suggesting that HCN channels are involved in the peristaltic contraction of ureteral ICCs, which may be an important reason for peristaltic dysfunction in ureteric tuberculosis.
Highlights
The main physiological function of spontaneous contraction of the ureter is to promote continuous transport of urine to the bladder
To study the effects of ZD7288 treatment on the ureteral smooth muscle contractility, the ureter smooth muscle strip tension assay was performed with samples from the control group (Fig. 1a) and from the experimental group (Fig. 1d)
Ureteral tuberculosis, which develops secondarily to renal tuberculosis due to tuberculosis infection, produces specific inflammation that affects spontaneous peristaltic movement of the ureter, and in turn, these peristaltic changes increase the inflammation that eventually leads to renal atresia caused by ureteral fibrosis and results in irreversible loss of renal function
Summary
The main physiological function of spontaneous contraction of the ureter is to promote continuous transport of urine to the bladder. According to previous research data, studies showed that the bladder in vitro had spontaneous contractile function and could inhibit the contractions after adding ZD7288, which is a special hyperpolarization-activated cyclic nucleotidegated (HCN) channels blocker. Urinary bladder interstitial cells of Cajal (ICCs) act as pacemaker cells to generate the physiological contraction of the bladder; the expression of HCN channels in ICCs is an important mechanism for generating spontaneous excitation–contraction in the bladder [3–12]. Previous studies have shown that ICCs have a similar distribution and expression pattern in the ureter [13–16] compared to the bladder. There was a correlation between the function of the ureter and the expression of ICCs in different pathological conditions [2, 15–19]. If HCN channels were expressed in ureteral ICCs, could the variability in HCN channel expression impact the spontaneous contraction of the ureter under pathological conditions? If HCN channels were expressed in ureteral ICCs, could the variability in HCN channel expression impact the spontaneous contraction of the ureter under pathological conditions? To answer this question, we performed the following preliminary study
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