# The RAGE Inhibitor TTP488 (Azeliragon) Improves Diabetic Bladder Dysfunction in Leptin-Deficient Obese Mice

## TL;DR

Blocking the RAGE receptor with TTP488 improves bladder function in obese diabetic mice without affecting weight or blood sugar.

## Contribution

This study is the first to show that RAGE inhibition can treat diabetic bladder dysfunction in leptin-deficient mice.

## Key findings

- TTP488 reduced AGE and MG-H1 levels in bladder tissues without altering RAGE levels.
- TTP488 reversed collagen accumulation and improved bladder contractility in diabetic mice.
- TTP488 normalized antioxidant enzyme activities in bladder tissues of ob/ob mice.

## Abstract

The advanced glycation end product (AGE)–RAGE axis has been implicated in the pathophysiology of diabetic bladder dysfunction (DBD). However, no previous studies have explored the effects of RAGE blockade on this condition. Here, we explored the effects of the selective RAGE inhibitor TTP488 (azeliragon) at the functional and molecular levels of bladder dysfunction in ob/ob leptin-deficient mice. Female B6.V-Lep ob/JUnib (ob/ob) and wild-type (WT) C57BL/6 mice were used as lean controls. Treatment with TTP488 in ob/ob mice resulted in no changes in body weight, fasting glucose, or insulin resistance; however, it reduced total AGE and MG-H1 levels without altering RAGE levels in bladder tissues. TTP488 normalized glyoxalase-1, glutathione reductase, glutathione peroxidase, and superoxide dismutase activities in bladder tissues. Marked increases in collagen intensity were also observed in ob/ob mice, an effect fully reversed by TTP488 treatment. TTP488 reduced total void volume, volume per void, and ex vivo bladder contractility in response to electrical-field stimulation and carbachol. Our finding that TTP488 mitigates DBD in ob/ob mice supports the proposal that RAGE blockade could serve as a promising therapeutic strategy for managing DBD.