Renal protective effect of SGLT2 inhibitor dapagliflozin alone and in combination with irbesartan in a rat model of diabetic nephropathy

Lasker

et al. 2020

Sci Rep

The antidiabetic drug canagliflozin is reported to possess several cardioprotective effects. However, no studies have investigated protective effects of canagliflozin in isoprenaline (ISO)-induced cardiac oxidative damage-a model mimicking sympathetic nervous system (SNS) overstimulation-evoked cardiac injuries in humans. Therefore, we investigated protective effects of canagliflozin in ISOinduced cardiac oxidative stress, and their underlying molecular mechanisms in Long-Evans rat heart and in HL-1 cardiomyocyte cell line. Our data showed that ISO administration inflicts pro-oxidative changes in heart by stimulating production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In contrast, canagliflozin treatment in ISO rats not only preserves endogenous antioxidants but also reduces cardiac oxidative stress markers, fibrosis and apoptosis. Our Western blotting and messenger RNA expression data demonstrated that canagliflozin augments antioxidant and anti-inflammatory signaling involving AMP-activated protein kinase (AMPK), Akt, endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In addition, canagliflozin treatment attenuates pro-oxidative, pro-inflammatory and proapoptotic signaling mediated by inducible nitric oxide synthase (iNOS), transforming growth factor beta (TGF-β), NADPH oxidase isoform 4 (Nox4), caspase-3 and Bax. Consistently, canagliflozin treatment improves heart function marker in ISO-treated rats. In summary, we demonstrated that canagliflozin produces cardioprotective actions by promoting multiple antioxidant and antiinflammatory signaling. Canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, belongs to a new class of antidiabetic drugs prescribed for the management of type 2 diabetes mellitus (T2DM) 1. Accumulating evidence suggests that canagliflozin exhibits a range of cardiovascular effects that are independent of glucose lowering. According to recent preclinical and clinical data, canagliflozin treatment significantly reduced risk of cardiovascular death, myocardial infarction (MI), stroke and hospitalization due to heart failure in both diabetic and non-diabetic subjects 2-5. Proposed mechanisms for cardiovascular benefits of canagliflozin include improvement of cardiac metabolism and diastolic function, reduction of vascular stiffness, and an overall reduction of blood pressure 5-9. A growing body of evidence suggests that canagliflozin possess antioxidant and anti-inflammatory actions in various cellbased and animal models 10-14. Canagliflozin was shown to reduce vascular inflammation and atherosclerosis by

Section: Discussionmentioning

confidence: 99%

Canagliflozin attenuates isoprenaline-induced cardiac oxidative stress by stimulating multiple antioxidant and anti-inflammatory signaling pathways

Lasker

et al. 2020

Sci Rep

“…Recent studies reported that SGLT2 inhibitors had a renal protective effect in animal models of diabetic nephropathy 122–124 . The renal protective effects of SGLT2 inhibitors also have been shown in clinical trials 9,125,126 .…”

Section: Therapeutic Potential Of Sglt1 and Sglt2 Inhibitionmentioning

confidence: 97%

“…In preclinical studies in diabetic animal models, the SGLT2 inhibitors decreased fasting and non‐fasting glucose levels, hemoglobin A1c levels, and blood pressure, and improved glucose intolerance 114–117 . Furthermore, SGLT2 inhibitors have a different mechanism from the other antidiabetic drugs, as described above, and can be used in combination with those drugs, as well as in monotherapy for the treatment of type 2 diabetes 118–122 .…”

Section: Therapeutic Potential Of Sglt1 and Sglt2 Inhibitionmentioning

confidence: 99%

Sodium–glucose cotransporters: Functional properties and pharmaceutical potential

Sano

Shinozaki

Ohta

2020

J of Diabetes Invest

Glucose is the most abundant monosaccharide, and an essential source of energy for most living cells. Glucose transport across the cell membrane is mediated by two types of transporters: facilitative glucose transporters (gene name: solute carrier 2A) and sodiumglucose cotransporters (SGLTs; gene name: solute carrier 5A). Each transporter has its own substrate specificity, distribution, and regulatory mechanisms. Recently, SGLT1 and SGLT2 have attracted much attention as therapeutic targets for various diseases. This review addresses the basal and functional properties of glucose transporters and SGLTs, and describes the pharmaceutical potential of SGLT1 and SGLT2.

“…Despite widespread use of these therapeutics, more than 30% of patients with type 2 diabetes mellitus (T2DM) develop DKD [ 3 ]. Recently, inhibition of the sodium-glucose co-transporter 2 (SGLT2) in kidneys, a more recent and novel therapeutic approach to lower hyperglycemia, has been shown to slow progression of DKD in preclinical models and clinical studies, either as stand-alone or combination therapy, including DPP-4 inhibitors, GLP-1 receptor antagonist, or ACEi/ARBs [ 12 – 14 ]; however the mechanisms are not entirely known [ 15 – 21 ]. SGLT2 inhibitors induce glycosuria by reducing reabsorption of glucose in proximal tubules, and evidence from clinical trials indicates that they also exert cardiovascular protection [ 17 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

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

Aroor

Das

Carpenter

et al. 2018

Cardiovasc Diabetol

123

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.