Adenosine A(1) 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 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.

Fig. 1

Diabetes-induced glomerular hyperfiltration is blunted in A₁R–/– mice. Parameters were assessed in WT and littermate A₁R–/– mice on a standard NaCl diet (1%) at 4 weeks after STZ or vehicle injection. GFR was assessed in awake mice. The absence of A₁Rs did not affect the STZ-diabetes-induced increase in blood glucose, food and fluid intake, or the modest reduction in body weight. The lack of A₁Rs, however, blunted the STZ-diabetes-induced increase in GFR. n = 10–12/group. * p < 0.05. NS = Not significant.

Fig. 2

Plasma aldosterone concentrations and changes in salt and fluid intake and body weight in WT and A₁R–/– mice in response to low and high NaCl intake. WT and littermate A₁R–/– mice were switched from a control NaCl diet (1% NaCl) to a low- (0.1% NaCl) or high- (4%) NaCl diet at about 5 weeks after STZ or vehicle injection. The absence of A₁Rs did not affect salt intake or the ability to maintain body weight in response to low or high NaCl intake. n = 5–6/group. ^a p < 0.05 vs. low NaCl; ^b p < 0.05 vs. WT on same diet.

Fig. 3

The NaCl paradox of the diabetic kidney is present in WT mice but absent in A₁R–/– mice. Paired GFR measurements were performed in awake WT and littermate A₁R–/– mice under the control NaCl diet (1% NaCl, single measurements are shown from the experiments summarized in fig. 1) and after 1 week of low (0.1% NaCl) or high (4%) NaCl intake. Measurements on the 1% NaCl diet were taken at 4 weeks after STZ or vehicle injection. One week later, the mice were switched to a low- or high-NaCl diet. In STZ-diabetic WT mice, switching from control to low or high NaCl intake induced significantly different and opposing responses in GFR, i.e. a rise in response to low NaCl and a fall in response to high NaCl intake. Moreover, the kidney weight was greater in STZ-diabetic WT mice on low versus high NaCl intake. In STZ-diabetic A₁R–/– mice, the NaCl paradox of GFR and the greater kidney weight in mice on the low-NaCl diet were not detectable. n = 5–6/group. * p < 0.05.