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

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. 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. Translational StatementConsiderable interest exists in identifying the actions of incretin-based therapies beyond glucose lowering, particularly in the kidney. In this study, we showed that mice with genetic disruption of Glp1r spontaneously develop chronic renal injury. We demonstrate that superimposition of diabetes in Glpr1r-deficient mice accelerated diabetic kidney disease (DKD) development and the phenotypic changes could be reversed by deletion of the proinflammatory receptor for advanced glycation end products (Ager). Treatment of diabetic mice with a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, reduced kidney injury. Unbiased exploration using single-cell transcriptomics of kidney identified that GLP-1R agonism with liraglutide in diabetic mice remodeled a network of nutrient synthesis and transport, and promoted redox sensing signals in the proximal tubule, podocyte, and macrophage cell populations. Liraglutide treatment led to dampening of inflammatory signals in macrophages. This study demonstrates the importance of intact GLP-1R signaling in the maintenance of kidney homeostasis, provides a rationale for investigating GLP-1RA for the treatment of non-DKDs, and highlights the glucose-independent renal benefits of GLP-1RA. Considerable interest exists in identifying the actions of incretin-based therapies beyond glucose lowering, particularly in the kidney. In this study, we showed that mice with genetic disruption of Glp1r spontaneously develop chronic renal injury. We demonstrate that superimposition of diabetes in Glpr1r-deficient mice accelerated diabetic kidney disease (DKD) development and the phenotypic changes could be reversed by deletion of the proinflammatory receptor for advanced glycation end products (Ager). Treatment of diabetic mice with a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, reduced kidney injury. Unbiased exploration using single-cell transcriptomics of kidney identified that GLP-1R agonism with liraglutide in diabetic mice remodeled a network of nutrient synthesis and transport, and promoted redox sensing signals in the proximal tubule, podocyte, and macrophage cell populations. Liraglutide treatment led to dampening of inflammatory signals in macrophages. This study demonstrates the importance of intact GLP-1R signaling in the maintenance of kidney homeostasis, provides a rationale for investigating GLP-1RA for the treatment of non-DKDs, and highlights the glucose-independent renal benefits of GLP-1RA. Diabetic kidney disease (DKD) occurs in up to 40% of individuals with diabetes and remains the primary cause of kidney failure worldwide,1Cooper M.E. Pathogenesis, prevention, and treatment of diabetic nephropathy.Lancet. 1998; 352: 213-219Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar, 2Shaw J.E. Sicree R.A. Zimmet P.Z. Global estimates of the prevalence of diabetes for 2010 and 2030.Diabetes Res Clin Pract. 2010; 87: 4-14Abstract Full Text Full Text PDF PubMed Scopus (5271) Google Scholar, 3Parving H.H. Lewis J.B. Ravid M. et al.Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective.Kidney Int. 2006; 69: 2057-2063Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar accounting for at least a third of all cases requiring renal replacement therapy.4Thomas M.C. Cooper M.E. Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease.Nat Rev Nephrol. 2016; 12: 73-81Crossref PubMed Scopus (389) Google Scholar The outlook for DKD has improved over recent decades as a result of improved blood glucose control, blood pressure management with an emphasis on renin-angiotensin system blockade, and, more recently, the use of sodium-glucose cotransporter-2 inhibitors. However, a significant proportion of individuals with diabetes will still progress to kidney failure or die prematurely from a cardiovascular event.5Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7703) Google Scholar, 6UK Prospective Diabetes Study GroupTight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.BMJ. 1998; 317: 703-713Crossref PubMed Scopus (0) Google Scholar, 7Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research GroupEffect of intensive therapy on the microvascular complications of type 1 diabetes mellitus.JAMA. 2002; 287: 2563-2569Crossref PubMed Google Scholar Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone, which is produced and released by the L cells of the gastrointestinal tract after meal ingestion.8Baggio L.L. Drucker D.J. Biology of GLP-1 and Full Text Full Text PDF PubMed Scopus Google Scholar GLP-1 from a the L.L. Drucker D.J. Biology of GLP-1 and Full Text Full Text PDF PubMed Scopus Google J.B. Glucagon-like therapies for type 2 diabetes: a on Scopus Google Scholar of GLP-1 et peptide-1 receptor agonist renal through action blood glucose in a model of type 1 PubMed Scopus Google et of GLP-1R signaling in diabetic and Int. Full Text Full Text PDF PubMed Scopus Google Scholar and more as the and in of et and cardiovascular in type 2 2016; PubMed Google Scholar and the with a in et and renal in type 2 diabetes: an of the Full Text Full Text PDF PubMed Scopus Google Scholar using GLP-1R agonists (GLP-1RA) as liraglutide and actions of GLP-1 receptor agonism. 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