Abstract
Altered nucleoside levels may be linked to pathogenic signaling through adenosine receptors. We hypothesized that adenosine dysregulation contributes to fibrosis in diabetic kidney disease. Our findings indicate that high glucose levels and experimental diabetes decreased uptake activity through the equilibrative nucleoside transporter 1 (ENT1) in proximal tubule cells. In addition, a correlation between increased plasma content of adenosine and a marker of renal fibrosis in diabetic rats was evidenced. At the cellular level, exposure of HK2 cells to high glucose, TGF-β and the general adenosine receptor agonist NECA, induced the expression of profibrotic cell activation markers α-SMA and fibronectin. These effects can be avoided by using a selective antagonist of the adenosine A3 receptor subtype in vitro. Furthermore, induction of fibrosis marker α-SMA was prevented by the A3 receptor antagonist in diabetic rat kidneys. In conclusion, we evidenced the contribution of purinergic signaling to renal fibrosis in experimental diabetic nephropathy.
Highlights
Diabetes mellitus is produced by a chronic metabolic unbalance and its incidence rate has dramatically increased worldwide [1]
Using the epithelial cell line HK2, derived from human proximal tubules, it was determined that the adenosine uptake activity was largely mediated by the equilibrative sodiumindependent transporters (ENTs) compared to the negligible activity mediated by the concentrative nucleoside transporters (CNTs)
The uptake mediated by the equilibrative nucleoside transporter-1 (ENT1) was far more significant in comparison to the transport activity mediated by ENT2 in these cells (Fig 1A)
Summary
Diabetes mellitus is produced by a chronic metabolic unbalance and its incidence rate has dramatically increased worldwide [1]. Diabetic nephropathy (DN) is a long-term complication affecting up to 30–40% of diabetic patients and is the major cause of end-stage renal disease worldwide [2]. DN is a major risk factor for cardiovascular disease and can be a life threatening condition. The economic and social impact of the illness is high, due to the fact that DN. Adenosine Mediates Renal Fibrosis no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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