Adiponectin Signaling in Bladder Function

About This Grant

Abstract: Lower urinary tract symptoms (LUTS) not only impact the quality of life for the patients, but also impose a significant economic burden on society. LUTS is strongly associated with obesity and metabolic syndrome. However, the underlying molecular mechanisms of this association are unclear. Adipose tissue not only functions as an energy storage organ but also plays an important endocrine role by releasing adipokines to signal other organs, thereby regulating metabolism, inflammation, and cellular functions. Whether dysregulated adipokines lead to LUTS is unknown. Adiponectin (ADPN) is the most abundant adipokine, which exhibits an inverse association with obesity/metabolic syndrome. ADPN plays a crucial role in metabolic homeostasis through its anti-diabetic and anti-inflammatory effects, and mice lacking ADPN develop insulin resistance, metabolic syndrome, and a shortened lifespan. Our data demonstrated that global ADPN-deleted mice exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle (BSM) contractility, with corresponding metabolic and purinergic pathway changes. Furthermore, activation of ADPN receptor (AdpioR) signaling by agonist AdipoRon profoundly inhibited acute BSM contraction. These data indicate that ADPN plays an important role in regulating acute BSM contractility and chronic BSM cell phenotype. We therefore propose a novel hypothesis that dysregulation of ADPN signaling constitutes a major pathway leading to LUTS associated with obesity/metabolic syndrome. We will examine our hypothesis through the following two aims. Aim 1. We will determine the distinct role of adipocyte-secreted and BSM- autocrine ADPN in bladder function. We will create an adipose-specific ADPN knockout model and a smooth muscle-specific ADPN knockout model to test its role in regulating BSM contractile function and BSM cell phenotype. We will further determine the plasma ADPN levels and molecular mechanisms in these distinct ADPN deletion mouse models. AdipoRon, a potent AdipoR agonist will be used to test whether the bladder abnormalities in a specific ADPN-deleted model can be reversed. Aim 2. We will define ADPN signaling pathways in the bladder. Both ADPN receptors 1 (AdipoR1) and 2 (AdipoR2) are expressed in BSM cells. We propose that activation of the cell membrane expressed AdipoR1 sequentially regulates downstream PLC/IP3/ Ca2+/CaMKKb/AMPK pathway, which acutely regulates BSM contraction-relaxation by modulating the balance of myosin light chain kinase and/or myosin light chain phosphatase. We also hypothesize that intracellular localized AdipoR2 mediates PPARa transcriptional activation of genes for cell metabolism and proliferation, leading to chronic regulation of BSM cell phenotype. We will further examine how ADPN signaling impacts insulin signaling and thus contributes to BSM phenotypic and functional changes. We have created smooth muscle-specific AdipoR1 and AdipoR2 mouse models to test our hypothesis. Understanding these novel mechanisms for obesity/metabolic syndrome-associated LUTS will facilitate novel therapeutic strategies.