Unlocking the Potential: The Activation of Angiotensin Type 2 Receptor (AT2R) Prevents Diabetic Kidney Disease in a Sex-Specific Manner

Diabetes is characterized by high blood sugar and is often associated with complications as a result of poor blood sugar control including heart disease and kidney failure. Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and a major cause of kidney failure in Canada. People with kidney failure (end-stage of kidney disease) require treatment by artificial kidney (dialysis) or by kidney transplant to survive. While treatments exist, they often fail to stop the disease from getting worse-especially in a way that accounts for biological differences between male and female. Research shows that men and women may develop DKD differently, respond differently to treatment, and have different disease outcomes, but we still don't fully understand why. This project focuses on a protein in the body called the angiotensin II type 2 receptor (AT2R), which helps protect the heart and kidneys. When this protective receptor is lost or reduced, it may trigger harmful processes in kidney cells, including cell aging, scarring, and cell death. We will study how this happens differently in male and female. We are also testing a promising drug called compound 21 (C21), which activates AT2R, to see if it can slow or prevent DKD progression in a sex-specific way. To do this, we will use a well-established mouse model of diabetes, as well as male and female kidney cell lines in our lab. These models allow us to study the disease without the added complications of obesity or other metabolic issues. By investigating these biological sex differences, our goal is to discover new ways to treat DKD more effectively in both men and women. The findings from this research will support future clinical trials and help guide more personalized, sex-informed treatment strategies for people living with diabetes and kidney disease in Canada.