Ackermann Teresa F, Boini Krishna M, Völkl Harald, Bhandaru Madhuri, Bareiss Petra M, Just Lothar, Vallon Volker, Amann Kerstin, Kuhl Dietmar, Feng Yuxi, Hammes Hans-Peter, Lang Florian
Dept. of Physiology, Univ. of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
Am J Physiol Renal Physiol. 2009 Apr;296(4):F859-66. doi: 10.1152/ajprenal.90238.2008. Epub 2009 Jan 21.
The hyperglycemia of diabetes mellitus increases the filtered glucose load beyond the maximal tubular transport rate and thus leads to glucosuria. Sustained hyperglycemia, however, may gradually increase the maximal renal tubular transport rate and thereby blunt the increase of urinary glucose excretion. The mechanisms accounting for the increase of renal tubular glucose transport have remained ill-defined. A candidate is the serum- and glucocorticoid-inducible kinase SGK1. The kinase has been shown to stimulate Na(+)-coupled glucose transport in vitro and mediate the stimulation of electrogenic intestinal glucose transport by glucocorticoids in vivo. SGK1 expression is confined to glomerula and distal nephron in intact kidneys but may extend to the proximal tubule in diabetic nephropathy. To explore whether SGK1 modifies glucose transport in diabetic kidneys, Akita mice (akita(+/-)), which develop spontaneous diabetes, have been crossbred with gene-targeted mice lacking SGK1 on one allele (sgk1(+/-)) to eventually generate either akita(+/-)/sgk1(-/-) or akita(+/-)/sgk1(+/+) mice. Both akita(+/-)/sgk1(-/-) and akita(+/-)/sgk1(+/+) mice developed profound hyperglycemia (>20 mM) within approximately 6 wk. Body weight and plasma glucose concentrations were not significantly different between these two genotypes. However, urinary excretion of glucose and urinary excretion of fluid, Na(+), and K(+), as well as plasma aldosterone concentrations, were significantly higher in akita(+/-)/sgk1(-/-) than in akita(+/-)/sgk1(+/+) mice. Studies in isolated perfused proximal tubules revealed that the electrogenic glucose transport was significantly lower in akita(+/-)/sgk1(-/-) than in akita(+/-)/sgk1(+/+) mice. The data provide the first evidence that SGK1 participates in the stimulation of renal tubular glucose transport in diabetic kidneys.
糖尿病的高血糖症会使滤过的葡萄糖负荷增加，超过肾小管最大转运速率，从而导致糖尿。然而，持续性高血糖症可能会逐渐提高肾小管最大转运速率，进而减弱尿糖排泄的增加。导致肾小管葡萄糖转运增加的机制仍不明确。一种可能的因素是血清和糖皮质激素诱导激酶SGK1。该激酶在体外已被证明能刺激钠耦联葡萄糖转运，并在体内介导糖皮质激素对肠道电生性葡萄糖转运的刺激作用。在完整肾脏中，SGK1的表达局限于肾小球和远端肾单位，但在糖尿病肾病中可能会扩展至近端小管。为了探究SGK1是否会改变糖尿病肾脏中的葡萄糖转运，已将自发发生糖尿病的阿基塔小鼠（akita(+/-)）与一个等位基因缺失SGK1的基因靶向小鼠（sgk1(+/-)）进行杂交，最终培育出akita(+/-)/sgk1(-/-)或akita(+/-)/sgk1(+/+)小鼠。akita(+/-)/sgk1(-/-)和akita(+/-)/sgk1(+/+)小鼠在大约6周内均出现了严重的高血糖症（>20 mM）。这两种基因型的小鼠体重和血糖浓度没有显著差异。然而，akita(+/-)/sgk1(-/-)小鼠的尿糖排泄、尿液、钠、钾排泄以及血浆醛固酮浓度均显著高于akita(+/-)/sgk1(+/+)小鼠。对分离灌注的近端小管的研究表明，akita(+/-)/sgk1(-/-)小鼠的电生性葡萄糖转运显著低于akita(+/-)/sgk1(+/+)小鼠。这些数据首次证明SGK1参与了糖尿病肾脏中肾小管葡萄糖转运增强的过程。
