Supported Research

Lay Abstract

Kidney Renin-Angiotensin System (RAS) and Sodium-Glucose Co-transporter 2 (SGLT2) in Diabetes Persistent hypertension and diabetes are two major risk factors for the development and progression of end-stage kidney disease (ESKD), accounting for 75% of all ESKD cases in Canada and the USA. ESKD is a major risk factor for myocardial infarction and stroke. Chronic treatment with inhibitors of a hormonal system called renin-angiotensin system (RAS) and the sodium-glucose co-transporter 2 (Sglt2) (main protein in the kidney that reabsorbs 90% glucose filtered through the glomerulus) are the most effective treatments in retarding ESKD progression though underlying mechanisms remain incompletely understood. In addition to systemic RAS, the presence of local kidney RAS is now well documented and accepted. We (Dr. John Chan’s group) recently reported that angiotensin II (the vasoactive peptide of the RAS) stimulates the expression of Sglt2 in kidney cells in vivo and in vitro and it is inhibited by losartan (an Ang II receptor blocker). This proposal concerns the physiological role(s) of kidney RAS and its relationship with Sglt2 expression in ESKD development and progression in type 1 diabetic mice as well as the underlying molecular mechanism(s) of how Ang II up-regulates Sglt2 expression in human renal proximal tubular cells in vitro. Our studies will increase our knowledge and understanding of the pathological role of kidney RAS and SGLT2 in ESKD progression, thereby contributing directly to improved clinical treatment of patients with diabetes. Furthermore, our data will determine whether intrarenal RAS would be a druggable target in diabetes.