Diabetes-induced hyperfiltration in adenosine A(1)-receptor deficient mice lacking the tubuloglomerular feedback mechanism

J Sällström, P-O Carlsson, B B Fredholm, E Larsson, A E G Persson, F Palm
Acta Physiologica 2007, 190 (3): 253-9

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 A(1)-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 (> or =20 mm). Normoglycaemic animals had a similar GFR independent of genotype (A1AR(+/+) 9.3 +/- 0.5 vs. A1AR(-/-) 10.1 +/- 0.8 microL min(-1)g(-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 microL min(-1)g(-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.

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