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Aim Diabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. This study investigates whether chronic stimulation of the adenosine A2a receptor (A2a AR) protects kidney function in insulinopenic diabetic rats. Methods Streptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A2a AR agonist CGS21680 throughout the four-week diabetes duration. Kidney function was thereafter investigated, and urine and plasma samples were collected for analysis of protein, oxidative stress and inflammatory markers. Results Glomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A2a AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A2a AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A2a AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF- α and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness. Conclusion Chronic A2a AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia. [ABSTRACT FROM AUTHOR]

Aim Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. Sustained hyperglycaemia is also closely associated with kidney hypertrophy and increased electrolyte and glucose reabsorption in the proximal tubule. In this study, we investigated the role of the increased tubular sodium/glucose cotransport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback ( TGF) mechanism, we used adenosine A1-receptor deficient (A1 AR−/−) mice known to lack a functional TGF mechanism and compared the results to corresponding wild-type animals (A1 AR+/+). Methods Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate ( GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose cotransporters were inhibited by phlorizin 30 min prior to GFR measurements. Results Normoglycaemic animals had a similar GFR independent of genotype (A1 AR+/+ 233 ± 11 vs. A1 AR−/− 241 ± 25 μL min−1), and induction of diabetes resulted in glomerular hyperfiltration in both groups (A1 AR+/+ 380 ± 25 vs. A1 AR−/− 336 ± 35 μL min−1; both P < 0.05). Phlorizin had no effect on GFR in normoglycaemic mice, whereas it reduced GFR in both genotypes during diabetes (A1 AR+/+ 365 ± 18 to 295 ± 19, A1 AR−/− 354 ± 38 to 199 ± 15 μL min−1; both P < 0.05). Notably, the reduction was more pronounced in the A1 AR−/− ( P < 0.05). Conclusion This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point. [ABSTRACT FROM AUTHOR]

Aims: Glomerular hyperfiltration is commonly found in diabetic patients early after the onset of disease. This is one of the first indications of the development of progressive diabetic nephropathy. It has been proposed that glomerular hyperfiltration is caused by decreased delivery of electrolytes to the macula densa due to the increased sodium and glucose reabsorption in the proximal tubule, which would increase the glomerular filtration rate (GFR) via the tubuloglomerular feedback (TGF) mechanism. In this study, we investigated the role of TGF in diabetes-induced glomerular hyperfiltration by inducing diabetes in adenosine A1-receptor knockout (A1AR−/−) mice known to lack a functional TGF mechanism. Methods: Diabetes was induced by alloxan (75 mg kg−1 bw) injected into the tail vein. The 24-hour urinary electrolyte excretion was measured in metabolic cages, the GFR determined by inulin clearance under isoflurane-anaesthesia, and histological changes evaluated. Results: All alloxan-treated animals developed hyperglycaemia (≥20 mm). Normoglycaemic animals had a similar GFR independent of genotype (A1AR+/+ 9.3 ± 0.5 vs. A1AR−/− 10.1 ± 0.8 μL min−1g−1 bw) and diabetes resulted in similar glomerular hyperfiltration in both groups (A1AR+/+ 14.0 ± 1.7, n = 9 vs. A1AR−/− 15.3 ± 1.9 μL min−1g−1 bw). Diabetic animals had a similar tendency to develop interstitial fibrosis, whereas the glomerular volume was similar in both genotypes, and unaltered by diabetes. Conclusions: This study shows that the A1AR−/− mice develop diabetes-induced glomerular hyperfiltration, demonstrating that the TGF mechanism is not the major cause of the development of hyperfiltration. Furthermore, the hyperfiltration in the present study was not related to alterations in the glomerular filtration area. [ABSTRACT FROM AUTHOR]