Defining the Role of Angiotensin II Type 2 Receptor in Bladder Physiology and Pathophysiology with Mouse Models

About This Grant

PROJECT SUMMARY The complex communication mechanisms involved in bladder function are not fully understood. Due to this lack of physiological understanding, bladder diseases have remained challenging to treat, resulting in severe detriment to patient quality of life, particularly in the case of interstitial cystitis/bladder pain syndrome (IC/BPS). To address this, I aim to contribute to the ongoing investigation of the role of renin-angiotensin signaling in the bladder to inform future therapeutic strategies. Angiotensin II (Ang II) is the primary effector molecule of the renin-angiotensin system, and action on either of its receptors, Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R), has been shown to elicit major effects in other organ systems. While Ang II signaling research in the bladder has primarily focused on defining the role of AT1R in mediating contractions and pathological effects on bladder tissue, AT2R should also be considered for its potential protective effects. Despite the understanding that AT2R counteracts the pathological impact of AT1R in other organ systems, the role of AT2R in the bladder remains largely unknown. Preliminary investigations have demonstrated that AT2R is expressed in the bladder, and one investigation showed that blocking AT2R in mice worsened the pathological effects in a cystitis model. However, there has not been a comprehensive investigation solely regarding the presence and role of AT2R in the bladder. Given these preliminary findings, I hypothesize that AT2R has a functional role in the bladder, and its activation can alleviate hyperalgesia and bladder dysfunction associated with cystitis conditions. This work will be conducted with two main aims: Aim 1 will provide a physiological evaluation by using naïve mouse bladder tissue to characterize the presence and location of AT2R mRNA expression and define the role of AT2R in ex vivo contractile responses through pharmacological manipulation of AT2R activity; Aim 2 will explore the role of AT2R in a pathophysiological bladder condition in vivo through chronic administration of an AT2R agonist, C21, in a cystitis mouse model. The effect of AT2R activation will be evaluated through voiding function, abdominal hypersensitivity, molecular changes, and ex vivo contractile responses. This work begins to uncover the role of AT2R in bladder physiology and pathology and is the first to broach the potential of AT2R as a therapeutic target for bladder diseases such as IC/BPS. Expanding the knowledge of angiotensin signaling in bladder dysfunction provides a foundation for pharmacological and non-pharmacological interventions that could improve patient outcomes and quality of life. The proposed research will help me develop as an independent scientist, providing me the opportunity to lead an experiment and gain the technical skills needed for a career in science. As a PhD student in the Joint Department of Biomedical Engineering at the Medical College of Wisconsin and Marquette University under mentorship from Dr. Aaron Mickle and Dr. Justin Grobe, I have all the tools necessary to complete this fellowship effectively and obtain preparation for my career.