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. 2014 Feb;210(2):440-5.
doi: 10.1111/apha.12152. Epub 2013 Aug 27.

Inhibition of sodium-linked glucose reabsorption normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A₁-receptor deficient mice

J Sällström  1 , T Eriksson, B B Fredholm, A E G Persson, F Palm
Affiliations

Inhibition of sodium-linked glucose reabsorption normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A₁-receptor deficient mice

J Sällström et al. Acta Physiol (Oxf). 2014 Feb.

Abstract

Aim: Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. Sustained hyperglycaemia is also closely associated with kidney hypertrophy and increased electrolyte and glucose reabsorption in the proximal tubule. In this study, we investigated the role of the increased tubular sodium/glucose cotransport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback (TGF) mechanism, we used adenosine A₁-receptor deficient (A1AR(-/-)) mice known to lack a functional TGF mechanism and compared the results to corresponding wild-type animals (A1AR(+/+)).

Methods: Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate (GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose cotransporters were inhibited by phlorizin 30 min prior to GFR measurements.

Results: Normoglycaemic animals had a similar GFR independent of genotype (A₁AR(+/+) 233 ± 11 vs. A₁AR(-/-) 241 ± 25 μL min(-1)), and induction of diabetes resulted in glomerular hyperfiltration in both groups (A₁AR(+/+) 380 ± 25 vs. A₁AR(-/-) 336 ± 35 μL min(-1); both P < 0.05). Phlorizin had no effect on GFR in normoglycaemic mice, whereas it reduced GFR in both genotypes during diabetes (A₁AR(+/+) 365 ± 18 to 295 ± 19, A₁AR(-/-) 354 ± 38 to 199 ± 15 μL min(-1); both P < 0.05). Notably, the reduction was more pronounced in the A₁AR(-/-) (P < 0.05).

Conclusion: This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point.

Keywords: adenosine; diabetes mellitus; glomerular hyperfiltration; tubuloglomerular feedback.

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Figures

Figure 1
Figure 1
Glomerular filtration rate in adenosine A1-receptor wild-type (A1AR+/+) and A1-receptor deficient (A1AR−/−) mice with different plasma glucose status (Series 1). * denotes p<0.05 compared to corresponding normoglycemic group.
Figure 2
Figure 2
Effect of phlorizin on glomerular filtration rate and plasma glucose levels in normoglycemic and diabetic adenosine A1-receptor wild-type (A1AR+/+) and A1-receptor deficient (A1AR−/−) mice (Series 2). * denotes p<0.05 compared to corresponding normoglycemic group, # denotes p<0.05 compared to vehicle within the same genotype and plasma glucose status, and † denotes p<0.05 compared to phlorizin-treated wild-type group.
See this image and copyright information in PMC

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