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首页> 外文期刊>Cell and Tissue Research >Impact of an SGLT2-loss of function mutation on renal architecture, histology, and glucose homeostasis
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Impact of an SGLT2-loss of function mutation on renal architecture, histology, and glucose homeostasis

机译：SGLT2失去功能突变对肾架构，组织学和葡萄糖稳态的影响

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摘要

Inhibitors of sodium/glucose co-transporter 2 (SGLT2) are currently in clinical use for type 2 diabetes (T2D) treatment due to their anti-hyperglycemic effect exerted by the inhibition of glucose reabsorption in the kidney. Inhibition of SGLT2 is associated with improvement of renal outcomes in chronic kidney disease associated with T2D. Our study aimed to describe the renal-specific phenotypic consequences of the SGLT2-loss of function "Jimbee" mutation within the Slc5a2 mouse gene in a non-diabetic/non-obese background. The Jimbee mice displayed reduced body weight, glucosuria, polyuria, polydipsia, and hyperphagia but were normoglycemic, with no signs of baseline insulin resistance or renal dysfunction. Histomorphological analysis of the kidneys revealed a normal architecture and morphology of the renal cortex, but shrinkage of the glomerular and tubular apparatus, including Bowman's space, glomerular tuft, mesangial matrix fraction, and proximal convoluted tubule (PCT). Immunofluorescent analysis of renal sections showed that SGLT2 was absent from the apical membrane of PCT of the Jimbee mice but remnant positive vesicles were detected within the cytosol or at the perinuclear interface. Renal localization and abundance of GLUT1, GLUT2, and SGLT1 were unchanged in the Jimbee genotype. Intriguingly, the mutation did not induce hepatic gluconeogenic gene expression in overnight fasted mice despite a high glucose excretion rate. The Jimbee phenotype is remarkably similar to humans with SLC5A2 mutations and provides a useful model for the study of SGLT2-loss of function effects on renal architecture and physiology, as well as for identifying possible novel roles for the kidneys in glucose homeostasis and metabolic reprogramming.
机译：钠/葡萄糖共转运体2抑制剂（SGLT2）目前临床上用于2型糖尿病（T2D）的治疗，因为其通过抑制肾脏中的葡萄糖再吸收而产生的降血糖作用。在与T2D相关的慢性肾病中，抑制SGLT2与改善肾脏预后相关。我们的研究旨在描述非糖尿病/非肥胖背景下Slc5a2小鼠基因中SGLT2功能丧失“Jimbee”突变的肾脏特异性表型后果。Jimbee小鼠表现出体重减轻、糖尿、多尿、多饮和贪食，但血糖正常，没有基线胰岛素抵抗或肾功能不全的迹象。肾脏的组织形态学分析显示，肾皮质的结构和形态正常，但肾小球和肾小管的收缩，包括鲍曼间隙、肾小球簇、系膜基质成分和近曲小管（PCT）。肾脏切片的免疫荧光分析显示，Jimbee小鼠PCT的顶膜上没有SGLT2，但在胞浆内或核周界面检测到残余的阳性小泡。在Jimbee基因型中，GLUT1、GLUT2和SGLT1的肾脏定位和丰度没有变化。有趣的是，尽管在夜间禁食的小鼠中葡萄糖排泄率很高，但该突变并没有诱导肝脏糖异生基因的表达。Jimbee表型与SLC5A2突变的人类非常相似，为研究SGLT2功能丧失对肾脏结构和生理学的影响，以及确定肾脏在葡萄糖稳态和代谢重编程中可能的新作用提供了有用的模型。

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  • 来源
    《Cell and Tissue Research》 |2021年第2期|共17页
  • 作者

    Hughes Corey B.; Mussman George M.; Ray Phil; Bunn Robert C.; Cornea Virgilius; Thrailkill Kathryn M.; Fowlkes John L.; Popescu Iuliana;

  • 作者单位

    Univ Kentucky Coll Med Barnstable Brown Diabet Ctr 900 S Limestone CTW469 Lexington KY 40536;

    Univ Kentucky Coll Med Barnstable Brown Diabet Ctr 900 S Limestone CTW469 Lexington KY 40536;

    Univ Kentucky Coll Med Barnstable Brown Diabet Ctr 900 S Limestone CTW469 Lexington KY 40536;

    Univ Kentucky Coll Med Barnstable Brown Diabet Ctr 900 S Limestone CTW469 Lexington KY 40536;

    Univ Kentucky Med Ctr Dept Pathol 800 Rose St MS117 Lexington KY 40536 USA;

    Univ Kentucky Coll Med Barnstable Brown Diabet Ctr 900 S Limestone CTW469 Lexington KY 40536;

    Univ Kentucky Coll Med Barnstable Brown Diabet Ctr 900 S Limestone CTW469 Lexington KY 40536;

    Univ Kentucky Coll Med Barnstable Brown Diabet Ctr 900 S Limestone CTW469 Lexington KY 40536;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
  • 关键词

    SGLT2; Kidney; Mutation; Phenotype; Gluconeogenesis;

    机译：SGLT2;肾脏;突变;表型;葡糖生成;

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