Reno-Protective Effect of GLP-1 Receptor Agonists in Type1 Diabetes: Dual Action on TRPC6 and NADPH Oxidases.

Natalie Youssef,Assaad Eid,Sami Azar,Nassim Fares,Hilda Ghadieh,Rachel Njeim,Mohamed Noureldein,Frederic Harb

doi:10.3390/biomedicines9101360

Natalie Youssef, Assaad Eid + Show 6 more

Open Access

https://doi.org/10.3390/biomedicines9101360

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Journal: Biomedicines	Publication Date: Sep 30, 2021
Citations: 12	License type: CC BY 4.0

Affiliation: American University of Beirut

Abstract

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.

Highlights

Diabetes mellitus is a leading cause of mortality worldwide
T1DM rats treated with liraglutide, metformin, or their combination have a significant decrease in blood urea nitrogen (BUN) and serum creatinine (SCr) levels when compared with the untreated T1DM rats (Figure 1A–C)
Periodic Acid-Schiff (PAS) staining was performed on kidney tissues sections, and the results show that T1DM development in rats is associated with an increase in sclerosis and fibrosis as indicated by the black arrows in both the glomerular and tubular compartments of the diabetic kidneys

Summary

Introduction

Diabetes mellitus is a leading cause of mortality worldwide. It is associated with deleterious complications that affect the eyes (retinopathy), nerves (neuropathy), kidneys (nephropathy), heart, and blood vessels causing dysfunction of the affected organs.Diabetes imposes a major economic burden on the global healthcare system [1].A hallmark of diabetic nephropathy, termed diabetic kidney disease (DKD), is the disruption of the glomerular filtration barrier (GFB) and thickening of the glomerular basement membrane (GBM) [2]. Diabetes mellitus is a leading cause of mortality worldwide. It is associated with deleterious complications that affect the eyes (retinopathy), nerves (neuropathy), kidneys (nephropathy), heart, and blood vessels causing dysfunction of the affected organs. Diabetes imposes a major economic burden on the global healthcare system [1]. A hallmark of diabetic nephropathy, termed diabetic kidney disease (DKD), is the disruption of the glomerular filtration barrier (GFB) and thickening of the glomerular basement membrane (GBM) [2]. A central actor for these pathological mechanisms is podocytes; their loss has a fatal impact on the GFB, as podocyte loss cannot be compensated, and is irreversible [3]. The actin cytoskeleton and associated proteins such as nephrin are essential for podocytes to sustain the integrity of the slit diaphragm, and thereby maintain adequate filtration [4]

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