Abstract
Diabetic nephropathy (DN) is considered the main cause of kidney disease in which myofibroblasts lead to renal fibrosis. Macrophages were recently identified as the major source of myofibroblasts in a process known as macrophage–myofibroblast transition (MMT). Adenosine levels increase during DN and in vivo administration of MRS1754, an antagonist of the A2B adenosine receptor (A2BAR), attenuated glomerular fibrosis (glomerulosclerosis). We aimed to investigate the association between A2BAR and MMT in glomerulosclerosis during DN. Kidneys/glomeruli of non-diabetic, diabetic, and MRS1754-treated diabetic (DM+MRS1754) rats were processed for histopathologic, transcriptomic, flow cytometry, and cellular in vitro analyses. Macrophages were used for in vitro cell migration/transmigration assays and MMT studies. In vivo MRS1754 treatment attenuated the clinical and histopathological signs of glomerulosclerosis in DN rats. Transcriptomic analysis demonstrated a decrease in chemokine-chemoattractants/cell-adhesion genes of monocytes/macrophages in DM+MRS1754 glomeruli. The number of intraglomerular infiltrated macrophages and MMT cells increased in diabetic rats. This was reverted by MRS1754 treatment. In vitro cell migration/transmigration decreased in macrophages treated with MRS1754. Human macrophages cultured with adenosine and/or TGF-β induced MMT, a process which was reduced by MRS1754. We concluded that pharmacologic blockade of A2BAR attenuated some clinical signs of renal dysfunction and glomerulosclerosis, and decreased intraglomerular macrophage infiltration and MMT in DN rats.
Highlights
Due to the increasing incidence rate of diabetes worldwide [1,2], a rise in the occurrence of diabetes-associated pathologies is predicted [3,4,5]
Due to the benefits associated with in vivo A2B adenosine receptor (A2B AR) blockade in Diabetic nephropathy (DN) rats, we proposed that the decrease in glomerular fibrosis and the improvement in renal function are due to decreased infiltration and myofibroblastic transdifferentiation of monocytes/macrophages in the glomerulus
Since TGF-β stimuli can induce macrophage–myofibroblast transition (MMT) [30,35,39,40,41,42] we evaluated the effect of adenosine and/or the blockade of A2B AR activation on human macrophages incubated with TGF-β for seven days
Summary
Due to the increasing incidence rate of diabetes worldwide [1,2], a rise in the occurrence of diabetes-associated pathologies is predicted [3,4,5]. Regardless of the treatment used, the progression of DN leads to renal fibrosis [11], which irreversibly remodels the parenchyma tissue replacing it with extracellular matrix (ECM), thereby losing functionality [12]. The pathophysiological events that trigger renal fibrosis are still unknown, this process is orchestrated by myofibroblasts, cells which have the capacity to generate pro-fibrotic mediators and to deposit ECM in damaged tissue [11,16,17,18]. Using experimental models of CKD it has been proposed that pericytes, resident fibroblasts of the kidney and bone marrow mononuclear cells (BM-MNCs), could undergo a mesenchymal transition process during renal fibrosis [27,28,29,30,31,32]. Cytokines and molecules secreted by kidney-resident cells contribute to monocyte/macrophage infiltration in the tubule-interstitium and the glomerulus [11,36]
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