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.

中文翻译：

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SGLT2-功能丧失突变对肾脏结构、组织学和葡萄糖稳态的影响

钠/葡萄糖协同转运蛋白 2 (SGLT2) 的抑制剂目前在临床上用于 2 型糖尿病 (T2D) 治疗，因为它们通过抑制肾脏中的葡萄糖重吸收发挥抗高血糖作用。抑制 SGLT2 与改善与 T2D 相关的慢性肾病的肾脏结局有关。我们的研究旨在描述非糖尿病/非肥胖背景中 Slc5a2 小鼠基因内 SGLT2 功能丧失“Jimbee”突变的肾脏特异性表型后果。Jimbee 小鼠的体重减轻、糖尿、多尿、烦渴和食欲亢进，但血糖正常，没有基线胰岛素抵抗或肾功能障碍的迹象。肾脏的组织形态学分析显示肾皮质的结构和形态正常，但肾小球和肾小管器官的收缩，包括鲍曼氏间隙、肾小球簇、系膜基质部分和近曲小管 (PCT)。肾脏切片的免疫荧光分析表明，Jimbee 小鼠 PCT 的顶膜中不存在 SGLT2，但在细胞质内或核周界面处检测到残留的阳性囊泡。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，尽管葡萄糖排泄率很高，但该突变并未在隔夜禁食小鼠中诱导肝脏糖异生基因表达。Jimbee 表型与具有 SLC5A2 突变的人类非常相似，并为研究 SGLT2 功能丧失对肾脏结构和生理学的影响提供了一个有用的模型，