Blockade of the Adenosine A(3) Receptor Attenuates Caspase 1 Activation in Renal Tubule Epithelial Cells and Decreases Interleukins IL-1 beta and IL-18 in Diabetic Rats

Garrido W.; Jara C.; Torres A.; Suarez R.; Cappelli C.; Oyarzún C.; Quezada C.; Martín R.S.

Abstract

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-1 beta and IL-18, meanwhile when adenosine deaminase was administered, there was a non-selective attenuation of the inflammatory mediators IL-1 beta, 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 NF kappa B in the renal tubular epithelium of diabetic rats, both events that are involved in regulating the production and activation of IL-1 beta 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 alpha-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.

Más información

Título según WOS: Blockade of the Adenosine A(3) Receptor Attenuates Caspase 1 Activation in Renal Tubule Epithelial Cells and Decreases Interleukins IL-1 beta and IL-18 in Diabetic Rats
Título según SCOPUS: Blockade of the adenosine A3 receptor attenuates caspase 1 activation in renal tubule epithelial cells and decreases interleukins IL-1? and IL-18 in diabetic rats
Título de la Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volumen: 20
Número: 18
Editorial: MDPI Open Access Publishing
Fecha de publicación: 2019
Idioma: English
DOI:

10.3390/ijms20184531

Notas: ISI, SCOPUS