Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products–induced inflammation

利拉鲁肽 炎症 受体 胰高血糖素样肽1受体 医学 内分泌学 内科学 糖尿病 肾脏疾病 2型糖尿病 兴奋剂
作者
Karly C. Sourris,Yi Ding,Scott Maxwell,Annas Al‐Sharea,Phillip Kantharidis,Muthukumar Mohan,Carlos J. Rosado,Sally A. Penfold,Claus Haase,Yangsong Xu,Josephine M. Forbes,Simon Crawford,Georg Ramm,Brooke E. Harcourt,Karin Jandeleit‐Dahm,Andrew Advani,Andrew Murphy,Daniel B. Timmermann,Anil Karihaloo,Lotte Bjerre Knudsen
出处
期刊:Kidney International [Elsevier BV]
卷期号:105 (1): 132-149 被引量:53
标识
DOI:10.1016/j.kint.2023.09.029
摘要

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.
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