1. Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation.
- Author
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Sourris KC, Ding Y, Maxwell SS, Al-Sharea A, Kantharidis P, Mohan M, Rosado CJ, Penfold SA, Haase C, Xu Y, Forbes JM, Crawford S, Ramm G, Harcourt BE, Jandeleit-Dahm K, Advani A, Murphy AJ, Timmermann DB, Karihaloo A, Knudsen LB, El-Osta A, Drucker DJ, Cooper ME, and Coughlan MT
- Subjects
- Rats, Mice, Animals, Receptor for Advanced Glycation End Products genetics, Receptor for Advanced Glycation End Products metabolism, Liraglutide pharmacology, Liraglutide therapeutic use, Glucagon-Like Peptide-1 Receptor genetics, Glucagon-Like Peptide 1 metabolism, Glucagon-Like Peptide 1 pharmacology, Glucagon-Like Peptide 1 therapeutic use, Inflammation, Diabetic Nephropathies etiology, Diabetic Nephropathies genetics, Diabetes Mellitus, Experimental metabolism
- Abstract
Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease. Mice with deletion of the GLP-1 receptor displayed an abnormal kidney phenotype that was accelerated by diabetes and improved with co-deletion of RAGE in vivo. Activation of the GLP-1 receptor pathway with liraglutide, an anti-diabetic treatment, downregulated kidney RAGE, reduced the expansion of bone marrow myeloid progenitors, promoted M2-like macrophage polarization and lessened markers of kidney damage in diabetic mice. Single cell transcriptomics revealed that liraglutide induced distinct transcriptional changes in kidney endothelial, proximal tubular, podocyte and macrophage cells, which were dominated by pathways involved in nutrient transport and utilization, redox sensing and the resolution of inflammation. The kidney-protective action of liraglutide was corroborated in a non-diabetic model of chronic kidney disease, the subtotal nephrectomised rat. Thus, our findings identify a novel glucose-independent kidney-protective action of GLP-1-based therapies in diabetic kidney disease and provide a valuable resource for exploring the cell-specific kidney transcriptional response ensuing from pharmacological GLP-1R agonism., (Copyright © 2023 International Society of Nephrology. All rights reserved.)
- Published
- 2024
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