Abstract
Diabetic bladder dysfunction (DBD) afflicts nearly half of diabetic patients, but effective treatment is lacking. In this study, IR-61, a novel heptamethine cyanine dye with potential antioxidant effects, was investigated to determine whether it can alleviate DBD. Rats were intraperitoneally injected with IR-61 or vehicle after diabetes was induced with streptozotocin. Before evaluating the effects of IR-61 in improving DBD by filling cystometry, we detected its distribution in tissues and subcellular organelles by confocal fluorescence imaging. Near infrared (NIR) imaging showed that IR-61 could accumulate at high levels in the bladders of diabetic rats, and confocal images demonstrated that it was mainly taken up by bladder smooth muscle cells (BSMCs) and localized in mitochondria. Then, filling cystometry illustrated that IR-61 significantly improved the bladder function of diabetic rats. The histomorphometry results showed that IR-61 effectively mitigated the pathological changes in bladder smooth muscle (BSM) in diabetic rats. Furthermore, IR-61 remarkably reduced the number of apoptotic BSMCs and the unfavorable expression of proteins related to the mitochondrial apoptotic pathway (Bcl-2, BAX, Cytochrome C, and cleaved Caspase-9) in diabetic rats. Moreover, the frozen section staining and transmission electron microscopy results proved that IR-61 significantly reduced the reactive oxygen species (ROS) levels and prevented the mitochondrial mass and morphology damage in the BSM of diabetic rats. In addition, IR-61 upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its associated antioxidant proteins in the BSM of diabetic rats. Together, these results indicate that IR-61 can improve the voiding function of rats with DBD by protecting the mitochondria of BSMCs from oxidative stress, which is possibly mediated through the activation of the Nrf2 pathway.
Highlights
The high incidence of urological complications associated with diabetes mellitus (DM), especially diabetic bladder dysfunction (DBD), has increasingly become a global public health concern (Arrellano-Valdez et al, 2014; Wessells et al, 2018)
Exploring the role of IR-61 in bladder smooth muscle cells (BSMCs) was the focus of this study
Transmission electron microscopy (TEM) images of bladder smooth muscle (BSM) showed that the BSMCs in the rats in the Diabetic bladder dysfunction (DBD) group exhibited increased mitochondrial calcification and degeneration, whereas IR-61 attenuated the damage to BSMC mitochondria observed in the diabetic rats (Figure 5G); these results showed that IR-61 had a protective effect on the mitochondria of BSMCs
Summary
The high incidence of urological complications associated with diabetes mellitus (DM), especially diabetic bladder dysfunction (DBD), has increasingly become a global public health concern (Arrellano-Valdez et al, 2014; Wessells et al, 2018). The symptoms of DBD include early urine storage problems, such as overactive bladder (OAB) with urgency incontinence, as well as late emptying disorders such as impaired bladder emptying, urinary retention, and overflow incontinence (Fayyad et al, 2009; Liu and Daneshgari, 2014; Wittig et al, 2019). Such different manifestations as overactive bladder and detrusor weakness may occur at different stages of DBD progression (Brown et al, 2005). It is necessary to develop novel and effective therapies
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