Phlorizin Pretreatment Reduces Acute Renal Toxicity in a Mouse Model for Diabetic Nephropathy
Phlorizin Pretreatment Reduces Acute Renal Toxicity in a Mouse Model for Diabetic Nephropathy
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DOI：
10.1074/jbc.m113.469486
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发表时间：
2013-09-20
影响因子：
4.8
通讯作者：
Creemers, John W. M.
中科院分区：
文献类型：
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作者：
Brouwers, Bas;Pruniau, Vincent P. E. G.;Creemers, John W. M.
链脲佐菌素(STZ)是糖尿病肾病动物模型中广泛使用的促糖尿病药物。然而，它对肾脏也有直接的细胞毒作用，因此很难区分糖尿病肾病和链脲佐菌素肾病。因此，需要一种改进的方法来产生用于糖尿病肾病研究的小鼠，快速和稳健地实现糖尿病状态，而不会直接对肾脏产生毒性。为探讨链脲佐菌素肾病的发病机制，采用大剂量链脲佐菌素诱导大鼠肾脏损伤模型。这导致胃排空延迟，至少部分原因是去脂酰Ghrelin清除受损。肾脏对STZ的摄取在很大程度上是由钠/葡萄糖共转运体(SGLT)介导的，因为SGLT抑制剂根茎苷可减少肾脏对STZ的摄取。因此，在不干扰β细胞毒性的情况下，肾脏和胃扩张的直接毒性效应得到了解决。此外，胰腺对STZ的摄取增加，从而降低了β细胞毒性的阈值，允许单独使用低剂量的非肾毒性STZ(70 mg/kg)。总之，这项研究为STZ对肾脏的毒性机制提供了新的见解，并建议了一种更有效的方案来诱导几乎或没有毒副作用的糖尿病肾病。
Streptozotocin (STZ) is widely used as diabetogenic agent in animal models for diabetic nephropathy (DN). However, it is also directly cytotoxic to kidneys, making it difficult to distinguish between DN-related and STZ-induced nephropathy. Therefore, an improved protocol to generate mice for DN studies, with a quick and robust achievement of the diabetic state, without direct kidney toxicity is required. To investigate the mechanism leading to STZ-induced nephropathy, kidney damage was induced with a high dose of STZ. This resulted in delayed gastric emptying, at least partially caused by impaired desacyl ghrelin clearance. STZ uptake in the kidneys is to a large extent mediated by the sodium/glucose cotransporters (Sglts) because the Sglt inhibitor phlorizin could reduce STZ uptake in the kidneys. Consequently, the direct toxic effects in the kidney and the gastric dilatation were resolved without interfering with the beta-cell toxicity. Furthermore, pancreatic STZ uptake was increased, hereby decreasing the threshold for beta-cell toxicity, allowing for single low non-nephrotoxic STZ doses (70 mg/kg). In conclusion, this study provides novel insights into the mechanism of STZ toxicity in kidneys and suggests a more efficient regime to induce DN with little or no toxic side effects.