Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury

Abstract

BackgroundArterial 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/methodsTen-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.ResultsCompared 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 of “reversion 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.ConclusionsEmpagliflozin 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.

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

“…14 In clinical trials, the use of SGLT2 inhibitors has been shown to reduce the quantity of epicardial adipose tissue (independently of effect on body weight), [35][36][37] and these drugs ameliorate the inflammation of adipose tissue surrounding the heart and great vessels 38,39 and the associated abnormalities of cardiac filling and aortic distensibility in both experimental and clinical HFpEF. 18,[40][41][42] Furthermore, SGLT2 inhibitors act to inhibit sodium reabsorption in the proximal renal tubules, in which the majority of renal sodium retention occurs [43][44][45] ; this action explains the marked reduction in plasma and/or interstitial volume and haemoconcentration seen in randomized controlled trials in type 2 diabetes. 25,46 Moreover, SGLT2 inhibitors can attenuate renal inflammation and fibrosis.…”

<p>Uric Acid and Arterial Stiffness</p>

“…149 Empagliflozin, a potent and highly selective SGLT-2 inhibitor, 150 was shown to reduce blood pressure and improve measures of arterial stiffness in diabetic patients. 151,152 However, the protective cardiovascular effect of SGLT-2 inhibitors has been shadowed by the results from postmarketing studies which indicate significant adverse effects, such as an increased risk of diabetic ketoacidosis and leg amputations. 153…”

Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat

“…Moreover, empagliflozin reduced the levels of CD36 and cardiotoxic lipids improving autophagy in the hearts of ZDF rats [28], and decreased aortic stiffness, renal resistivity index and kidney injury in T2D female mice [29]. Finally, empagliflozin ameliorated kidney injury in T2D female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness [29]. In addition, a redox-sensitive up-regulation of SGLT1 and 2 has been observed in coronary artery ECs in response to high glucose and H 2 O 2 leading to enhanced glucose uptake and induction of atherothrombotic responses [30].…”

“…Empagliflozin also significantly reduced left ventricle (LV) mass and LV systolic dilatation [25], decreased glucotoxicity thereby preventing the development of endothelial dysfunction, and reduced oxidative stress, cardiac fibrosis and exhibited anti-inflammatory effects in ZDF rats and mice [26,27]. Moreover, empagliflozin reduced the levels of CD36 and cardiotoxic lipids improving autophagy in the hearts of ZDF rats [28], and decreased aortic stiffness, renal resistivity index and kidney injury in T2D female mice [29]. Finally, empagliflozin ameliorated kidney injury in T2D female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness [29].…”