Hyperglucosuria induced by dapagliflozin augments bacterial colonization in the murine urinary tract.
Hyperglucosuria induced by dapagliflozin augments bacterial colonization in the murine urinary tract.
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DOI：
10.1111/dom.14064
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Subashchandrabose S
中科院分区：
文献类型：
--
作者：
Saenkham P;Jennings-Gee J;Hanson B;Kock ND;Adams LG;Subashchandrabose S
糖尿病是导致尿路感染（UTI）的主要危险因素。由尿路致病性大肠杆菌（UPEC）和其他尿路病原体引起的UTI是一种常见的感染性疾病，每年影响数百万人。格列净是通过增加尿糖排泄达到正常血糖的糖尿病药物。我们在小鼠模型中检测了达格列净诱导的高血糖对细菌UTI上升的影响。在经尿道接种UPEC或肺炎克雷伯菌之前，使用达格列净或卡格列净诱导非糖尿病成年雌性小鼠的高血糖。测定急性和慢性UTI期间的葡萄糖、细菌负荷、细胞因子、中性粒细胞动员和炎症。与对照组相比，在高糖小鼠的尿路中观察到UPEC负荷的显著增加。达格列净处理的小鼠发生菌血症，导致UPEC在脾脏和肝脏定植的频率高于对照组。高糖小鼠的慢性UTI导致肾衰竭的发生率增加。组织学评价显示，尽管细菌负荷显著增加，但达格列净治疗小鼠的膀胱和肾脏组织损伤仅适度增加。高糖小鼠尿液中性粒细胞动员较差。我们还观察到高血糖小鼠尿液和膀胱中IL-1β以及尿液中IL-6的延迟增加。试验接种K.与对照组相比，经达格列净处理的小鼠的膀胱、脾脏和肝脏中的细菌负荷也更高。总的来说，我们的结果表明，在非糖尿病雌性小鼠中，达格列净诱导的高血糖导致对严重UTI和尿路源性菌血症的易感性增加。
Diabetes is a leading risk factor for development of urinary tract infection (UTI). UTI caused by uropathogenic Escherichia coli (UPEC), and other uropathogens is a common infectious condition affecting millions of people annually. Gliflozins are diabetes medications that achieve normoglycemia by increasing urinary glucose excretion. We tested the effects of dapagliflozin-induced hyperglucosuria on ascending bacterial UTI in a mouse model. Dapagliflozin or canagliflozin was used to induce hyperglucosuria in non-diabetic adult female mice prior to transurethral inoculation with UPEC or Klebsiella pneumoniae. Glucose, bacterial load, cytokines, neutrophil mobilization, and inflammation during acute and chronic UTI were determined. Significant increase in UPEC load was observed in the urinary tract of hyperglucosuric mice, compared to controls. Dapagliflozin-treated mice developed bacteremia resulting in UPEC colonization of the spleen and liver at a higher frequency than controls. Chronic UTI in hyperglucosuric mice resulted in an increased incidence of renal abscesses. Histopathological evaluation revealed only modest increases in tissue damage in the urinary bladders, and kidneys of dapagliflozin-treated mice, despite profound increase in bacterial load. There was poor neutrophil mobilization to the urine of hyperglucosuric mice. We also observed a delayed increase of IL-1β in urine, and bladders, and IL-6 in urine of hyperglucosuric mice. Experimental inoculation with K. pneumoniae also revealed higher bacterial burden in the urinary bladder, spleen and liver from dapagliflozin-treated mice, compared to controls. Collectively, our results indicate that dapagliflozin-induced hyperglucosuria in non-diabetic female mice leads to increased susceptibility to severe UTI, and bacteremia of urinary tract origin.
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影响因子：
3.3
作者：
Ozer, Ahmet;Altuntas, Cengiz Z.;Daneshgari, Firouz
通讯作者：
Daneshgari, Firouz
DOI：
10.1038/nrmicro3432
发表时间：
2015-05
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
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通讯作者：
Hultgren SJ
影响因子：
4.4
作者：
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通讯作者：
Foxman, Betsy
影响因子：
16.2
作者：
Geerlings, SE;Meiland, R;Hoepelman, AIM
通讯作者：
Hoepelman, AIM
影响因子：
4.4
作者：
Patterson, JE;Andriole, VT
通讯作者：
Andriole, VT