Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
FASEB J. 2019 Jun;33(6):7192-7201. doi: 10.1096/fj.201801778RR. Epub 2019 Mar 8.
Hypomagnesemia (blood Mg concentration <0.7 mM) is a common electrolyte disorder in patients with type 2 diabetes (T2D), but the etiology remains largely unknown. In patients with T2D, reduced blood Mg levels are associated with an increased decline in renal function, independent of glycemic control and hypertension. To study the underlying mechanism of this phenomenon, we investigated the renal effects of hypomagnesemia in high-fat-diet (HFD)-fed mice. In mice fed a low dietary Mg, the HFD resulted in severe hypomagnesemia within 4 wk. Renal or intestinal Mg wasting was not observed after 16 wk on the diets. Despite the absence of urinary or fecal Mg loss, the HFD induced a reduction in the mRNA expression transient receptor potential melastatin type 6 in both the kidney and colon. mRNA expression of distal convoluted tubule (DCT)-specific genes was down-regulated by the LowMg-HFD, indicating atrophy of the DCT. The low dietary Mg resulted in severe HFD-induced proximal tubule phospholipidosis, which was absent in mice on a NormalMg-HFD. This was accompanied by albuminuria, moderate renal damage, and alterations in renal energy metabolism, including enhanced gluconeogenesis and cholesterol synthesis. In conclusion, this study shows that hypomagnesemia is a consequence of diet-induced obesity and insulin resistance. Moreover, hypomagnesemia induces major structural changes in the diabetic kidney, including proximal tubular phospholipidosis, providing a novel mechanism for the increased renal decline in patients with hypomagnesemic T2D.-Kurstjens, S., Smeets, B., Overmars-Bos, C., Dijkman, H. B., den Braanker, D. J. W., de Bel, T., Bindels, R. J. M., Tack, C. J. J., Hoenderop, J. G. J., de Baaij, J. H. F. Renal phospholipidosis and impaired magnesium handling in high-fat-diet-fed mice.
低镁血症（血液 Mg 浓度<0.7mM）是 2 型糖尿病（T2D）患者常见的电解质紊乱，但病因仍知之甚少。在 T2D 患者中，降低的血镁水平与肾功能下降有关，与血糖控制和高血压无关。为了研究这一现象的潜在机制，我们研究了低脂饮食（HFD）喂养的小鼠中低镁血症的肾脏效应。在低镁饮食喂养的小鼠中，HFD 在 4 周内导致严重的低镁血症。在饮食 16 周后，未观察到肾脏或肠道镁丢失。尽管没有尿镁或粪镁丢失，但 HFD 诱导了肾脏和结肠中瞬时受体电位 melastatin 型 6（TRPM6）的 mRNA 表达减少。低镁-HFD 下调了远曲小管（DCT）特异性基因的 mRNA 表达，表明 DCT 萎缩。低膳食镁导致严重的 HFD 诱导的近端小管磷脂沉积，而在正常镁-HFD 喂养的小鼠中则不存在。这伴随着白蛋白尿、中度肾损伤和肾能量代谢改变，包括增强的糖异生和胆固醇合成。总之，这项研究表明，低镁血症是饮食诱导的肥胖和胰岛素抵抗的结果。此外，低镁血症诱导糖尿病肾脏的主要结构变化，包括近端肾小管磷脂沉积，为低镁血症 T2D 患者肾功能下降增加提供了一种新的机制。-库尔斯特延斯，S.，斯梅茨，B.，奥弗马尔斯-博斯，C.，迪克曼，H. B.，德布兰克，D. J. W.，德贝尔，T.，宾德尔斯，R. J. M.，塔克，C. J. J.，霍恩德罗普，J. G. J.，德拜，J. H. F. 高脂肪饮食喂养的小鼠中的肾脏磷脂沉积和镁处理受损。
