Role of the receptor for advanced glycation end products (RAGE) in diabetic bladder dysfunction: Is it a new therapeutic target?

• Grant number: 23/09353-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2023
• End date: November 30, 2026
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Edson Antunes
• Grantee: Ákila Lara de Oliveira
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Diabetes Mellitus (DM) is a metabolic disorder associated with high blood glucose levels. DM leads to several complications in the body, including voiding dysfunction, referred to as diabetic bladder dysfunction (DBD) or diabetic cystopathy, a condition present in more than 50% of patients diagnosed with DM type 1 (DM1) or DM type 2 (DM2), particularly in those in chronic states and not therapeutically controlled. These voiding changes consist of different clinical manifestations, ranging from hyperactivity to hypoactivity of the detrusor smooth muscle. The pathophysiology of DBD is multifactorial and complex, and may involve changes in the detrusor and urothelium, as well as in blood vessels and autonomic nerves. During states of hyperglycemia, there is an increase in the levels of dicarbonyl compounds, such as methylglyoxal (MGO), and an increase in the generation of advanced glycation end products (AGEs), which are formed by the non-enzymatic binding (glycation) of the dicarbonyl compound to certain proteins, leading to their loss of function. AGEs interact with their receptor (RAGE; receptor for AGEs) and trigger a cascade of intracellular events, including increased oxidative stress, which has been implicated in the genesis of DBD. It is also known that glycation by MGO in extracellular matrix proteins, such as collagen, causes blood vessel rigidity and tissue remodeling, and similar mechanisms may be involved in changes in detrusor contractility in diabetes. Our group has recently shown that prolonged administration of MGO to healthy mice causes changes in voiding function such as increased bladder capacity and residual volume (in vivo tests), as well as in vitro detrusor hypercontractility, which are accompanied by increased generation of ROS and collagen content in bladder tissue. However, the literature on the role of activation of the MGO-AGE-RAGE axis in the voiding disorder of diabetes is practically nil. Preliminary data presented in this project (unpublished), carried out in obese and leptin-deficient diabetic (ob/ob) mice, showed that the levels and/or expression of MGO, AGEs, RAGE and collagen in the bladder are significantly elevated in relation to the wild-type group. With regard to voiding dysfunction, we noticed in the ob/ob mouse an increase in capacity (volume per urination) and detrusor contractile alterations, dependent on the time of diabetes, characterized as initial hypercontractility (8 and 12 weeks of age) and later hypocontractility (15 weeks). Thus, based on these data, we proposed new questions about the role of RAGE in bladder physiology and its relationship with DBD. The hypothesis of this study is that RAGE becomes a promising target of the cascade of events that lead to DBD, such as hyperglycemia, formation of dicarbonyl compounds and AGEs. Therefore, the general objective of this study is to analyze the importance of the AGEs-RAGE axis for DBD in models of DM1 (NOD mice) and DM2 (ob/ob and db/db mice). We will carry out techniques to evaluate the in vivo voiding profile and in vitro bladder contractility, which will be accompanied by biochemical and molecular markers of the MGO-AGEs-RAGE axis in the bladder. The aim is also to verify whether pharmacological interventions aimed at the inhibition of RAGE such as alagebrium chloride (ALT-711; "breaker" of AGEs), azeliragon (bioavailable RAGE inhibitor orally) and RAGE antagonist peptide (RAP) improve the function of the diabetic bladder.