Interaction of Caveolin-3 and HCN is involved in the pathogenesis of diabetic cystopathy.

Xingyou Dong,Longkun Li,Margot Damaser,Zhou Long,Xiaoyan Hu,Chao Wu,Qian Liu,Qingqing Wang,Teng Zhang,Jiang Zhao,Jia Li,Qixiang Song,Jingzhen Zhu

doi:10.1038/srep24844

Abstract

A growing body of research suggests that impaired bladder Cajal-like interstitial cells (ICCs) are a important component in the pathogenesis of diabetes-induced bladder dysfunction, although the molecular mechanisms have not been illustrated completely. The purpose of this study was to examine whether the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in ICCs-DM were responsible for the detrusor weak contractility of Diabetic cystopathy (DCP) and to study the possible mechanism of regulating the expression and function of HCN channels. HCN channels expression were decreased at the mRNA and protein levels. Forskolin (FSK), which can elevate intracellular cAMP levels, increased the density of the hyperpolarization-activated current and intracellular calcium concentration in both normal control (NC) rats and DCP rats, but the sensitivity of FSK on HCN channels was clearly down-regulated in DCP rats. The loss of caveolae and caveolin was in accordance with the decrease in HCN channels. Caveolin-3 co-localizes with and affects the expression and function of HCN. Taken together, these results indicate that the loss of caveolae and HCN channels in ICCs-DM is important in the pathogenesis of DCP. Increasing the number of caveolae to enhance the function of HCN channels may represent a viable target for the pharmacological treatment of DCP.

Highlights

Diabetic cystopathy (DCP) is one of the most important complications of diabetes and is characterized by a broad spectrum of lower urinary tract symptoms (LUTS), encompassing urinary urgency, frequency, and incontinence, which are primarily attributable to alterations in neuronal and urothelial detrusor dysfunction[1]
In the insulin tolerance tests (ITT), diabetic rats lacked a response to insulin at 30, 60, 90 and 120 minutes after intraperitoneal injection with insulin (Fig. 1A)
The major results reveal that the development of DCP was accompanied by significant decreases in the expression and function levels of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels

Summary

Introduction

Diabetic cystopathy (DCP) is one of the most important complications of diabetes and is characterized by a broad spectrum of lower urinary tract symptoms (LUTS), encompassing urinary urgency, frequency, and incontinence, which are primarily attributable to alterations in neuronal and urothelial detrusor dysfunction[1]. A growing number of researchers have argued that ICCs may function as a sensing network, receiving/sending signals from/to the urothelium and detrusor, modulating afferent bladder innervation or activating a spinal or intramural reflex, rather than acting directly as bladder pacemakers[12]. The different shapes and arrangements indicate that two groups of ICCs have different roles in the physiological function of the bladder[14]. Both groups of ICCs exhibit spontaneous electrical and Ca2+-signaling and respond to application of neurotransmitter substances including adenosine triphosphate and carbachol, differences in the ion channels expressed in bladder ICC subtypes have been demonstrated and this may be indicative of their distinctive functions. Contraction-related neuroreceptors, such as muscarinic acetylcholine receptors and purinergic receptors, have been identified in ICCs-DM and are directly involved in the regulation of bladder excitation and contractibility[15,16]

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