期刊
CARDIOVASCULAR DIABETOLOGY
卷 17, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12933-018-0750-8
关键词
Vascular stiffness; Renal resistivity; SGLT2; RECK; Pulsatility index
资金
- Boehringer Ingelheim Pharma
- U.S. Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development (ORD-BLRD) Service Award [I01-BX004220]
- Research Career Scientist Award [IK6BX004016-01]
- National Institutes of Health (NIH) [K01 HL 125503, R01 HL 088105, K08 HL 129074]
Background: Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). Materials/methods: Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n=17), untreated db/db (DbC, n=19) and EMPA-treated db/db mice (DbE, n=19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg(-1) day(-1), and fed for 5 weeks, initiated at 11 weeks of age. Results: Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression ofreversion inducing cysteine rich protein with Kazal motifs (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. Conclusions: Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.
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