Reno-Protective Effect of GLP-1 Receptor Agonists in Type1 Diabetes: Dual Action on TRPC6 and NADPH Oxidases
Natalie Youssef,
Mohamed Noureldein,
Rachel Njeim,
Hilda E. Ghadieh,
Frederic Harb,
Sami T. Azar,
Nassim Fares,
Assaad A. Eid
Affiliations
Natalie Youssef
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh, Beirut 1107-2020, Lebanon
Mohamed Noureldein
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh, Beirut 1107-2020, Lebanon
Rachel Njeim
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh, Beirut 1107-2020, Lebanon
Hilda E. Ghadieh
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh, Beirut 1107-2020, Lebanon
Frederic Harb
Department of Life and Earth Sciences, Faculty of Sciences, Lebanese University, Fanar, Jdeidat P.O. Box 90656, Lebanon
Sami T. Azar
American University of Beirut (AUB) Diabetes, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh, Beirut 1107-2020, Lebanon
Nassim Fares
Laboratory of Physiology and Physiopathology, Faculty of Medicine, Saint Joseph University of Beirut, Damas Street, 11-5076, Riad El-Solh, Beirut 1107-2180, Lebanon
Assaad A. Eid
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh, Beirut 1107-2020, Lebanon
Diabetic kidney disease (DKD), a serious diabetic complication, results in podocyte loss and proteinuria through NADPH oxidases (NOX)-mediated ROS production. DUOX1 and 2 are NOX enzymes that require calcium for their activation which enters renal cells through the pivotal TRPC channels. Hypoglycemic drugs such as liraglutide can interfere with this deleterious mechanism imparting reno-protection. Herein, we aim to investigate the reno-protective effect of GLP1 receptor agonist (GLP1-RA), via its effect on TRPC6 and NADPH oxidases. To achieve our aim, control or STZ-induced T1DM Sprague–Dawley rats were used. Rats were treated with liraglutide, metformin, or their combination. Functional, histological, and molecular parameters of the kidneys were assessed. Our results show that treatment with liraglutide, metformin or their combination ameliorates DKD by rectifying renal function tests and protecting against fibrosis paralleled by restored mRNA levels of nephrin, DUOX1 and 2, and reduced ROS production. Treatment with liraglutide reduces TRPC6 expression, while metformin treatment shows no effect. Furthermore, TRPC6 was found to be directly interacting with nephrin, and indirectly interacting with DUOX1, DUOX2 and GLP1-R. Our findings suggest that treatment with liraglutide may prevent the progression of diabetic nephropathy by modulating the crosstalk between TRPC6 and NADPH oxidases.
