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 A_2B adenosine receptor (A_2BAR), attenuated glomerular fibrosis (glomerulosclerosis). We aimed to investigate the association between A_2BAR 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 A_2BAR attenuated some clinical signs of renal dysfunction and glomerulosclerosis, and decreased intraglomerular macrophage infiltration and MMT in DN rats.

Diabetic nephropathy (DN) is the main cause of end-stage renal disease, which remains incurable. The progression of DN is associated with progressive and irreversible renal fibrosis and also high levels of adenosine. Our aim was to evaluate the effects of ADORA3 antagonism on renal injury in streptozotocin-induced diabetic rats. An ADORA3 antagonist that was administered in diabetic rats greatly inhibited the levels of inflammatory interleukins IL-1β and IL-18, meanwhile when adenosine deaminase was administered, there was a non-selective attenuation of the inflammatory mediators IL-1β, IL-18, IL-6, and induction of IL-10. The ADORA3 antagonist attenuated the high glucose-induced activation of caspase 1 in HK2 cells in vitro. Additionally, ADORA3 antagonisms blocked the increase in caspase 1 and the nuclear localization of NFκB in the renal tubular epithelium of diabetic rats, both events that are involved in regulating the production and activation of IL-1β and IL-18. The effects of the A3 receptor antagonist resulted in the attenuation of kidney injury, as evidenced by decreased levels of the pro-fibrotic marker α-SMA at histological levels and the restoration of proteinuria in diabetic rats. We conclude that ADORA3 antagonism represents a potential therapeutic target that mechanistically works through the selective blockade of the NLRP3 inflammasome.

Objetivo Determinar si el inflamasoma NLRP3 puede considerarse como opción de tratamiento para la enfermedad renal.Métodos Con el fin de encontrar bibliografía relacionada con la estructura del inflamasoma NLRP3, su función biológica y su relación con la enfermedad renal y otras (hipertensión, diabetes, gota, aterosclerosis, amiloidosis, enfermedad de Alzheimer), se realizó una revisión sistemática en dos bases de datos (PubMed y SciELO) con los términos: "NLRP3 inflammasome therapeutic for kidney disease" y "NLRP3 inflammasome in kidney disease" en PubMed, e "Iinflammasome" en SciELO.Resultados Se encontró un total de 146 documentos, de los cuales solo 34 concuerdan con la hipótesis de trabajo desarrollada con relación al inflamasoma NLRP3 como componente central de diversas enfermedades en seres humanos y con potencial uso terapéutico. El inflamasoma NLRP3 es responsable de la maduración de la interleucina inflamatoria pro-IL-1 β y IL-18, l cual puede darse por causa de materiales agregados o cristalinos (partículas), y por diversos microorganismos y toxinas derivadas de los mismos; sin embargo, los mecanismos de activación de este proceso siguen sin ser claros en la actualidad.Conclusiones Se propone estudiar nuevas terapias que se centren en la eliminación o inhibición de los componentes inflamasoma, de manera individual y conjunta.