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

Abstract

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 (A 1 , A 2A , A 2B and A 3 ) 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 A 2A receptors, which might be relevant for the development of hypertensive diabetic nephropathy. This study highlights the adenosine A 2A receptors as a potential target to explore to prevent and/or treat early diabetes-induced hyperfiltration, at least in hypertensive conditions.

Adenosine A2A and A3 Receptors as Targets for the Treatment of Hypertensive-Diabetic Nephropathy

“…In the present study, we observed that SHR-STZ rats treated with CADO (but not with DPSPX) for seven days showed higher expression of adenosine A 2A receptors in SG, PCT, and DCT than control SHR-STZ rats. Interestingly, this difference was observed in the same renal structures where we previously demonstrated a decrease in the expression of the adenosine A 2A receptor associated with the induction of diabetes in SHR when compared with normoglycemic SHR [ 29 ]. Furthermore, we previously reported that CADO treatment improved glucose metabolism (decreased hyperglycemia and glycosuria) and renal function (decreased proteinuria) [ 20 ].…”

“…As such, treatment with CADO is also associated with decreased renal fibrosis, which can be a result of increased anti-fibrotic adenosine A 2A receptors [ 4 , 48 ]. Taken together, these studies of our group, performed in the same experimental conditions, show that in SHR, induction of diabetes with STZ decreases the expression of renal adenosine A 2A receptors [ 29 ] and that exogenously stimulating adenosine receptors can partially restore that lessened expression of the adenosine A 2A receptor. This positive modulatory role of exogenous adenosine (here mimicked by CADO infusion) seems to be specific for the adenosine A 2A receptor since we observed no alteration in the expression of A 1 , A 2B , or A 3 receptors in these renal structures.…”

“…Furthermore, we previously reported that CADO treatment improved glucose metabolism (decreased hyperglycemia and glycosuria) and renal function (decreased proteinuria) [ 20 ]. As pointed out in our previous study, the downregulation of adenosine A 2A receptors in SHR-STZ rats (when compared with control non-diabetic SHR) [ 29 ] could be contributing to the observed increase in intraglomerular pressure leading to hyperfiltration and to the decrease in sodium reabsorption leading to diuresis and natriuresis. In the present study, we also show that SHR-STZ rats treated with CADO have less collagen deposition when compared with that observed in control SHR-STZ rats.…”

“…Immunohistochemistry was performed as previously described [ 29 , 34 , 35 ] with some modifications. Briefly, sections were dewaxed with toluene and rehydrated in a graded series of ethanol at room temperature (RT).…”

“…Kidney adenosine levels are markedly increased in diabetes [ 18 ], and the expression [ 22 , 26 , 27 , 28 ] and function [ 20 ] of renal adenosine receptors are altered in experimental diabetes. We previously showed that the adenosine A 2A receptor is downregulated in experimental diabetes associated with spontaneous hypertension [ 29 ]. However, there is no information on how endogenous or exogenous levels of adenosine regulate the expression of adenosine receptors in this context and what would be the functional relevance of that regulation.…”