A2BAR Antagonism Decreases the Glomerular Expression and Secretion of Chemoattractants for Monocytes and the Pro-Fibrotic M2 Macrophages Polarization during Diabetic Nephropathy
Year: 2023
Type: article
Abstract: Some chemoattractants and leukocytes such as M1 and M2 macrophages are known to be involved in the development of glomerulosclerosis during diabetic nephropathy (DN). In the course of diabetes, an altered and defective cellular metabolism leads to the increase in adenosine levels, and thus to changes in the polarity (M1/M2) of macrophages. MRS1754, a selective antagonist of the A2B adenosine receptor (A2BAR), attenuated glomerulosclerosis and decreased macrophage-myofibroblast transition in DN rats. Therefore, we aimed to investigate the effect of MRS1754 on the glomerular expression/secretion of chemoattractants, the intraglomerular infiltration of leukocytes, and macrophage polarity in DN rats. Kidneys/glomeruli of non-diabetic, DN, and MRS1754-treated DN rats were processed for transcriptomic analysis, immunohistopathology, ELISA, and in vitro macrophage migration assays. The transcriptomic analysis identified an upregulation of transcripts and pathways related to the immune system in the glomeruli of DN rats, which was attenuated using MRS1754. The antagonism of the A2BAR decreased glomerular expression/secretion of chemoattractants (CCL2, CCL3, CCL6, and CCL21), the infiltration of macrophages, and their polarization to M2 in DN rats. The in vitro macrophages migration induced by conditioned-medium of DN glomeruli was significantly decreased using neutralizing antibodies against CCL2, CCL3, and CCL21. We concluded that the pharmacological blockade of the A2BAR decreases the transcriptional expression of genes/pathways related to the immune response, protein expression/secretion of chemoattractants, as well as the infiltration of macrophages and their polarization toward the M2 phenotype in the glomeruli of DN rats, suggesting a new mechanism implicated in the antifibrotic effect of MRS1754.
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,780
Awards: SEVERAL MECHANISMS OF THERAPEUTIC RESISTANCE ARE REGULATED THROUGH ADENOSINE SIGNALING IN GLIOBLASTOMA STEM-LIKE CELLS, ROL DEL RECEPTOR DE ADENOSINA A2B EN LA CAPACIDAD DE INFILTRACION Y DIFERENCIACION MIOFIBROBLASTICA DE MONOCITOS/MACROFAGOS EN LA GLOMERULOESCLEROSIS DIABETICA, BLOCKADE OF PODOCYTE DEDIFFERENTIATION AND FIBROSIS IN DIABETIC NEPHROPATHY THROUGH ADENOSINE A2B RECEPTOR ANTAGONISM, G5828120061, G643743565, THE EFFECT OF DIABETES MELLITUS AND THE A2B ADENOSINE RECEPTOR ON THE POLARITY AND FIBROTIC FUNCTION OF MACROPHAGES IN IDIOPATHIC PULMONARY FIBROSIS, G8892238693, G960252883
OpenAlex ID: W4382369503