Research Article: Diabetes downregulates renal adenosine A2A receptors in an experimental model of hypertension

Date Published: May 31, 2019

Publisher: Public Library of Science

Author(s): Daniela Patinha, Carla Carvalho, Carla Abreu, Olga M. Cunha, Mariana C. Mota, Joana Afonso, António Albino-Teixeira, Carmen Diniz, Manuela Morato, Dulce Elena Casarini.


Studies on diabetic nephropathy rarely take into account that the co-existence of diabetes and hypertension is frequent and further aggravates the prognosis of renal dysfunction. Adenosine can activate four subtypes of adenosine receptors (A1, A2A, A2B and A3) and has been implicated in diabetic nephropathy. However, it is not known if, in hypertensive conditions, diabetes alters the presence/distribution profile of renal adenosine receptors. The aim of this work was to describe the presence/distribution profile of the four adenosine receptors in six renal structures (superficial/deep glomeruli, proximal/distal tubules, loop of Henle, collecting tubule) of the hypertensive kidney and to evaluate whether it is altered by diabetes. Immunoreactivities against the adenosine receptors were analyzed in six renal structures from spontaneously hypertensive rats (SHR, the control group) and from SHR rats with diabetes induced by streptozotocyin (SHR-STZ group). Data showed, for the first time, that all adenosine receptors were present in the kidney of SHR rats, although the distribution pattern was specific for each adenosine receptor subtype. Also, induction of diabetes in the SHR was associated with downregulation of adenosine A2A receptors, which might be relevant for the development of hypertensive diabetic nephropathy. This study highlights the adenosine A2A receptors as a potential target to explore to prevent and/or treat early diabetes-induced hyperfiltration, at least in hypertensive conditions.

Partial Text

Diabetes Mellitus joins a group of metabolic diseases characterized by hyperglycemia and associated with high morbidity and mortality rates. It has reached epidemic proportions; approximately 422 million people worldwide have diabetes[1] and this number will continue to escalate, with predictions to rise up to 592 million by the year of 2035[2]. It is estimated that almost 1/3 of all diabetic patients will develop diabetic nephropathy[3], the prime cause of end-stage renal disease which, therefore, has a great impact on the use of health resources and associated costs[4]. In its initial stage, diabetic nephropathy is mainly characterized by glomerular hyperfiltration and hypertrophy, basal membrane thickening and mesangial matrix expansion that then progress to glomerulosclerosis, persistent proteinuria and decreased glomerular filtration rate (GFR)[3]. Early hyperfiltration is a good predictor for the development of end-stage renal disease[5].

The presence/distribution profile of the adenosine receptor subtypes A1, A2A, A2B and A3 was characterized in kidney nephron of the SHR (our control group; a well-known hypertensive animal model[45, 46]) and compared to that observed in the SHR with STZ-induced diabetes.

The results of the present study reveal, for the first time, a differential expression and distribution pattern of the four adenosine receptor subtypes along the nephron of the SHR. Additionally and also innovative, this study uncovers a downregulation of renal adenosine A2A receptors caused by STZ-induced diabetes in hypertensive conditions.




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