Sällström J, Eriksson T, Fredholm B B, Persson A E G, Palm F
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Acta Physiol (Oxf). 2014 Feb;210(2):440-5. doi: 10.1111/apha.12152. Epub 2013 Aug 27.
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(+/+)).
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.
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).
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.
糖尿病患者在疾病发作后早期通常会出现肾小球高滤过，且可预测肾病的进展。持续性高血糖也与肾脏肥大以及近端小管中电解质和葡萄糖重吸收增加密切相关。在本研究中，我们调查了肾小管钠/葡萄糖共转运增加在糖尿病诱导的肾小球高滤过中的作用。为消除肾小管-肾小球反馈（TGF）机制的任何潜在混杂效应，我们使用了已知缺乏功能性TGF机制的腺苷A₁受体缺陷（A1AR(-/-)）小鼠，并将结果与相应的野生型动物（A1AR(+/+)）进行比较。
通过静脉推注四氧嘧啶诱导糖尿病。通过单次推注菊粉在清醒小鼠中测定肾小球滤过率（GFR）。在测量GFR前30分钟用根皮苷抑制钠/葡萄糖共转运体。
血糖正常的动物无论基因型如何GFR相似（A₁AR(+/+) 233±11对A₁AR(-/-) 241±25 μL min⁻¹），糖尿病诱导导致两组均出现肾小球高滤过（A₁AR(+/+) 380±25对A₁AR(-/-) 336±35 μL min⁻¹；均P<0.05）。根皮苷对血糖正常小鼠的GFR无影响，而在糖尿病期间它降低了两种基因型的GFR（A₁AR(+/+) 365±18至295±19，A₁AR(-/-) 354±38至199±15 μL min⁻¹；均P<0.05）。值得注意的是，A₁AR(-/-)中的降低更明显（P<0.05）。
本研究表明肾小管钠/葡萄糖重吸收增加对糖尿病诱导的高滤过很重要，且TGF机制不参与这些改变，而是起到减少与新设定点的任何偏差的作用。
