Department of Medicine, University of California, and Veterans Affairs San Diego Healthcare System , San Diego, California.
Department of Pathology, University of California, San Diego, California.
Am J Physiol Renal Physiol. 2020 May 1;318(5):F1100-F1112. doi: 10.1152/ajprenal.00607.2019. Epub 2020 Mar 2.
In the early proximal tubule, Na-glucose cotransporter 2 (SGLT2) mediates the bulk of renal glucose reabsorption. Gene deletion in mice () was used to determine the role of SGLT2 in acute kidney injury induced by bilateral ischemia-reperfusion (IR). In and littermate wild-type mice, plasma creatinine increased similarly on after IR. This was associated with an equal increase in both genotypes in the urinary kidney injury molecule-1-to-creatinine ratio, a tubular injury marker, and similarly reduced urine osmolality and increased plasma osmolality, indicating impaired urine concentration. In both IR groups, FITC-sinistrin glomerular filtration rate was equally reduced on , and plasma creatinine was similarly and incompletely restored on . In mice subjected to IR, fractional urinary glucose excretion was increased on but reduced and associated with normal renal Na-glucose cotransporter 1 (Sglt1) mRNA expression on , suggesting temporary SGLT1 suppression. In wild-type mice subjected to IR, renal Sglt1 mRNA was likewise normal on , whereas Sglt2 mRNA was reduced by 57%. In both genotypes, IR equally reduced urine osmolality and renal mRNA expression of the Na-K-2Cl cotransporter and renin on , suggesting thick ascending limb dysfunction, and similarly increased renal mRNA expression of markers of injury, inflammation, oxidative stress, and fibrosis (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, transforming growth factor-β1, NADPH oxidase-2, and collagen type 1). This was associated with equal increases in kidney histological damage scores and similar degree of capillary loss in both genotypes. The data indicate that genetic deletion of SGLT2 did not protect the kidneys in the initial injury phase or the subsequent recovery phase in a mouse model of IR-induced acute kidney injury.
在近端小管早期，钠-葡萄糖协同转运蛋白 2（SGLT2）介导大部分的肾脏葡萄糖重吸收。通过基因敲除小鼠（）来确定 SGLT2 在双侧缺血再灌注（IR）引起的急性肾损伤中的作用。在 和同窝野生型小鼠中，IR 后第 4 天血浆肌酐均相似地升高。这与两种基因型尿肾损伤分子-1 与肌酐比值的同等增加相关，这是一种肾小管损伤标志物，并且尿渗透压同样降低而血浆渗透压升高，表明尿液浓缩受损。在两个 IR 组中，FITC-辛糖肾小球滤过率在第 4 天同样降低，而血浆肌酐则在第 14 天同样且不完全恢复。在接受 IR 的 小鼠中，尿葡萄糖排泄分数在第 4 天增加，但在第 14 天减少且与正常肾 SGLT1（Sglt1）mRNA 表达相关，表明暂时 SGLT1 抑制。在接受 IR 的野生型小鼠中，肾 Sglt1 mRNA 在第 4 天也正常，而 Sglt2 mRNA 减少了 57%。在两种基因型中，IR 同样降低了尿渗透压和钠-钾-2Cl 协同转运蛋白和肾素的 mRNA 表达在第 14 天，表明厚升支功能障碍，并且同样增加了损伤、炎症、氧化应激和纤维化标志物的肾 mRNA 表达（肾损伤分子-1、中性粒细胞明胶酶相关脂质运载蛋白、单核细胞趋化蛋白-1、转化生长因子-β1、NADPH 氧化酶-2 和胶原 1）。这与两种基因型的肾组织学损伤评分同等增加和类似程度的毛细血管丢失相关。数据表明，在缺血再灌注诱导的急性肾损伤小鼠模型中，SGLT2 的基因缺失并没有在初始损伤阶段或随后的恢复阶段保护肾脏。
