Adenosine A(1) receptors determine glomerular hyperfiltration and the salt paradox in early streptozotocin diabetes mellitus

Nephron Physiol. 2009;111(3):p30-8. doi: 10.1159/000208211. Epub 2009 Mar 10.


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 A(1) receptor knockout mice (A(1)R-/-), which lack an immediate TGF response, to determine whether A(1)Rs are essential for early diabetic hyperfiltration and the salt paradox.

Methods: GFR was measured by inulin disappearance in conscious A(1)R-/- 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: A(1)R-/- 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 A(1)R-/-. A reciprocal relationship between GFR and dietary salt was found in WT diabetics, but not A(1)R-/- diabetics or nondiabetics of either strain.

Conclusion: A(1)Rs determine glomerular hyperfiltration and the salt paradox in early diabetes, which is consistent with the tubulocentric principle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aldosterone / blood
  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / physiopathology
  • Diet, Sodium-Restricted
  • Drinking
  • Eating
  • Feedback, Physiological
  • Glomerular Filtration Rate*
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Adenosine A1 / deficiency
  • Receptor, Adenosine A1 / genetics
  • Receptor, Adenosine A1 / metabolism*
  • Sodium Chloride, Dietary / metabolism*
  • Time Factors


  • Blood Glucose
  • Receptor, Adenosine A1
  • Sodium Chloride, Dietary
  • Aldosterone