TY - JOUR
T1 - Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products–induced inflammation
AU - Sourris, Karly C.
AU - Ding, Yi
AU - Maxwell, Scott S.
AU - Al-Sharea, Annas
AU - Kantharidis, Phillip
AU - Mohan, Muthu
AU - Rosado, Carlos
AU - Penfold, Sally
AU - Haase, Claus G
AU - Xu, Yangsong
AU - Forbes, Josephine M.
AU - Crawford, Simon A.
AU - Ramm, Georg
AU - Harcourt, Brooke E.
AU - Jandeleit-Dahm, Karin A.M.
AU - Advani, Andrew
AU - Murphy, Andrew J.
AU - Timmermann, Daniel B.
AU - Karihaloo, Anil
AU - Knudsen, Lotte Bjerre
AU - El-Osta, Assam
AU - Drucker, Daniel J.
AU - Cooper, Mark E.
AU - Coughlan, Melinda T.
N1 - Funding Information:
We thank Dr. Benjamin J. Lamont, Dr. Sih Min Tan, Dr. Gavin C. Higgins, Dr. Matthew Snelson, Dr. Runa Lindblom, Ms. Tuong-Vi Nguyen, Ms. Jenny Wang, Ms. Sarah Rosli, Mrs. Maryann Arnstein, and Dr. Anna Watson for their technical assistance and Dr. Henrik Sondergaard (Novo Nordisk) for his contribution to these studies. We would like to thank Emeritus Professor George Jerums (Austin Health and the University of Melbourne, Department of Medicine) for his input into these studies. We acknowledge the assistance of the Clive and Vera Ramaciotti Centre for Structural Cryo-Electron Microscopy, Monash University, Australia. This work was completed with support from the Diabetes Australia Research Program (Y12V-SOUK), Novo Nordisk (584803), and the Victorian Government's Operational Infrastructure Support Program. KCS has been supported by the Diabetes Australia Research Trust Viertel Postdoctoral Fellowship and a Diabetes Australia Research Program grant. MTC is the recipient of a Career Development Award from JDRF Australia, the recipient of the Australian Research Council Special Research Initiative in Type 1 Juvenile Diabetes. MEC and JMF are recipients of NHMRC Investigator Grants. AE-O is an NHMRC Senior Research Fellow (1154650). DJD is supported in part by a Banting and Best Diabetes Centre-Novo Nordisk Chair and a Sinai Health-Novo Nordisk Foundation fund in regulatory peptides and CIHR grant 154321. Figures were created with BioRender.com. KCS, YD, MTC, and MEC contributed equally to this work and are guarantors of this work. KCS is listed as first author because she was responsible for project management, overseeing the completion of all the experiments, running the mouse studies, analyzing the data, and completing all manuscript revisions. MTC is listed as last author as she supervised the experiments, analyzed the data and co-wrote the manuscript. KCS, YD, PK, MTC, and MEC each contributed to the conception and design of the study. KCS and YD conducted the experiments and analyzed the data. SSM and AE-O conducted the single-cell transcriptomic experiments and analysis. AJM and AA-s assisted with the bone marrow flow cytometric analysis. JMF, GR, SC, KJ-D, PK, MKM, CJR, SAP, and BEH assisted with the animal studies and drafting of the manuscript. DJD assisted with the provision of animals to establish colonies to complete the in vivo arm of the work. AA designed and ran the rat subtotal nephrectomy study and provided samples for further analysis. LBK, AK, DBT, and CH were involved in the study design. All of the authors have approved the final version of the manuscript.
Funding Information:
We thank Dr. Benjamin J. Lamont, Dr. Sih Min Tan, Dr. Gavin C. Higgins, Dr. Matthew Snelson, Dr. Runa Lindblom, Ms. Tuong-Vi Nguyen, Ms. Jenny Wang, Ms. Sarah Rosli, Mrs. Maryann Arnstein, and Dr. Anna Watson for their technical assistance and Dr. Henrik Sondergaard (Novo Nordisk) for his contribution to these studies. We would like to thank Emeritus Professor George Jerums (Austin Health and the University of Melbourne, Department of Medicine) for his input into these studies. We acknowledge the assistance of the Clive and Vera Ramaciotti Centre for Structural Cryo-Electron Microscopy, Monash University, Australia. This work was completed with support from the Diabetes Australia Research Program (Y12V-SOUK), Novo Nordisk (584803), and the Victorian Government’s Operational Infrastructure Support Program. KCS has been supported by the Diabetes Australia Research Trust Viertel Postdoctoral Fellowship and a Diabetes Australia Research Program grant. MTC is the recipient of a Career Development Award from JDRF Australia, the recipient of the Australian Research Council Special Research Initiative in Type 1 Juvenile Diabetes. MEC and JMF are recipients of NHMRC Investigator Grants. AE-O is an NHMRC Senior Research Fellow (1154650). DJD is supported in part by a Banting and Best Diabetes Centre-Novo Nordisk Chair and a Sinai Health-Novo Nordisk Foundation fund in regulatory peptides and CIHR grant 154321. Figures were created with BioRender.com.
Publisher Copyright:
© 2023 International Society of Nephrology
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
KW - diabetes
KW - diabetic kidney disease
KW - glucagon-like peptide-1
KW - kidney
KW - receptor for advanced glycation end products
UR - http://www.scopus.com/inward/record.url?scp=85180565244&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2023.09.029
DO - 10.1016/j.kint.2023.09.029
M3 - Article
C2 - 38069998
AN - SCOPUS:85180565244
SN - 0085-2538
VL - 105
SP - 132
EP - 149
JO - Kidney International
JF - Kidney International
IS - 1
ER -
