Background: In early type 1 diabetes mellitus, changes in proximal reabsorption influence glomerular filtration rate (GFR) through tubuloglomerular feedback (TGF). Due to TGF, a primary increase in proximal reabsorption causes early diabetic hyperfiltration, while a heightened sensitivity of the proximal tubule to dietary salt leads to the so-called salt paradox, where a change in dietary salt causes a reciprocal change in GFR (‘tubulocentric principle’). Here, experiments were performed in adenosine A1 receptor knockout mice (A1R–/–), which lack an immediate TGF response, to determine whether A1Rs are essential for early diabetic hyperfiltration and the salt paradox. Methods: GFR was measured by inulin disappearance in conscious A1R–/– and wild-type (WT) mice after 4 weeks of streptozotocin diabetes on a control NaCl diet (1%), and measurements were repeated after 6 days of equilibration on a low-NaCl (0.1%) or a high-NaCl (4%) diet. Results: A1R–/– and WT were similar with respect to blood glucose, dietary intakes and body weight changes on a given diet. Diabetic hyperfiltration occurred in WT, but was blunted in A1R–/–. A reciprocal relationship between GFR and dietary salt was found in WT diabetics, but not A1R–/– diabetics or nondiabetics of either strain. Conclusion: A1Rs determine glomerular hyperfiltration and the salt paradox in early diabetes, which is consistent with the tubulocentric principle.

Keywords:
Diabetes, Diabetic nephropathy, Glomerular hyperfiltration, Tubuloglomerular feedback, Salt paradox, Adenosine A1 receptor, Proximal tubule, Tubular hypothesis
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2009
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