Adenosine A1 receptors determine glomerular hyperfiltration and the salt paradox in early streptozotocin diabetes mellitus

Abstract

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 A 1R-/- diabetics or nondiabetics of either strain. Conclusion: A 1Rs determine glomerular hyperfiltration and the salt paradox in early diabetes, which is consistent with the tubulocentric principle. © 2009 S. Karger AG, Basel.