Reduced Adenosine Uptake and Its Contribution to Signaling that Mediates Profibrotic Activation in Renal Tubular Epithelial Cells: Implication in Diabetic Nephropathy

• Published in: PloS one 2016-01, Vol.11 (1), p.e0147430-e0147430
• Main Authors: Kretschmar, Catalina, Oyarzún, Carlos, Villablanca, Cristopher, Jaramillo, Catherinne, Alarcón, Sebastián, Perez, Gustavo, Díaz-Encarnación, Montserrat M, Pastor-Anglada, Marçal, Garrido, Wallys, Quezada, Claudia, San Martín, Rody
• Format: Article
• Language: English
• Subjects: Adenosina; Adenosine; Adenosine - metabolism; Animals; Antibiotics; Biochemistry; Biology and Life Sciences; Biomedical research; Cell activation; Cell Line; Cèl·lules epitelials; Diabetes; Diabetes mellitus; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; Diabetis; Epithelial cells; Epithelial Cells - metabolism; Fibronectin; Fibrosis; Fibrosis - metabolism; Genotype & phenotype; Glucose; Growth factors; Humans; Insulin; Kidney diseases; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidneys; Kinases; Male; Medicine and Health Sciences; Nephropathy; Nucleoside transporter; Nucleosides; Physical Sciences; Rats; Rats, Sprague-Dawley; Receptors; Rodents; Science; Signal Transduction; Signaling
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0147430

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.