Tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, suppresses renal damage in KKAy/Ta mice, obese and type 2 diabetic animals

Abstract

IntroductionAccording to the Diabetes Atlas, 7th edition, 2015, an estimated 415 million people worldwide had diabetes. 1 Among various vascular complications of diabetes, diabetic nephropathy is a global health challenge because it is a leading cause of end-stage renal disease, which could contribute to the increased risk of cardiovascular disease and death in diabetic patients. 2 Recently, inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been developed as a novel oral hypoglycaemic agent. 2 Since 90% of glucose filtered by the glomerulus is reabsorbed by a lowaffinity or high-capacity SGLT2 expressed on the apical membrane of proximal tubules at S1 and S2 segments, inhibitors of SGLT2 have a potential to improve hyperglycaemia in diabetic patients by promoting urinary glucose excretion. 2 Moreover, SGLT2 inhibitors have also been shown to ameliorate hypertension, hyperuricaemia and central obesity in patients with diabetes. 2 Since cardiometabolic derangements, including chronic hyperglycaemia and hypertension, are major risk factors for vascular complications in diabetes, treatment with SGLT2 inhibitors may be a promising strategy for preventing diabetic nephropathy. 2 Injury and apoptosis of proximal tubular cells have played a central role in the pathogenesis of tubular atrophy, tubulointerstitial fibrosis and atubular glomeruli, and these histological changes are most closely correlated with progression of renal dysfunction in diabetic patients. 2-4 Furthermore, we have found that increased Tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, suppresses renal damage in KKAy/Ta mice, obese and type 2 diabetic animals Yuji Ishibashi, Takanori Matsui and Sho-ichi Yamagishi Abstract Objective: Inhibitors of sodium-glucose cotransporter 2 ameliorate hyperglycaemia in diabetes by increasing urinary glucose excretion. However, the effects of sodium-glucose cotransporter 2 inhibitors on tubulointerstitial damage in diabetic nephropathy are not fully elucidated. We examined whether tofogliflozin, an inhibitor of sodium-glucose cotransporter 2, suppressed renal damage in KKAy/Ta mice, obese and type 2 diabetic animals. Materials and methods: Male 8-week-old KKAy/Ta mice or control C57BL/6J mice were kept on a standard diet with or without 0.015% tofogliflozin for 5 weeks. Blood glucose and blood pressure, body and kidney weight, urinary N-acetyl-β-d-glucosaminidase activity and albumin excretion levels were monitored. Results: Although tofogliflozin treatment did not affect blood pressure, body weight or serum creatinine values, it improved hyperglycaemia and blocked the elevation of urinary N-acetyl-β-d-glucosaminidase activity in KKAy/Ta diabetic mice at 9, 11 and 13 weeks. Furthermore, compared with control mice, urinary albumin excretion levels and kidney weight were increased in 13-week-old KKAy/Ta mice, both of which were suppressed by the treatment with tofogliflozin. Conclusion:Our present results demonstrated that tofogliflozin could suppress albuminuria and tubulointerstitial in...

Metabolic effects of Tofogliflozin are efficiently enhanced with appropriate dietary carbohydrate ratio and are distinct from carbohydrate restriction

“…According to the plasma Tofo concentrations in mice and in humans, the 0.015% Tofo dose given to the KK‐A y mice in this study is comparable to the therapeutic dose of 20 mg for patients with type 2 diabetes (Ishibashi et al. ). The animal care and experimental procedures were approved by the Animal Care Committee of Tokyo New Drug Research Laboratories, Kowa Company.…”

Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease

“…Interestingly, drugs that tightly regulate glucose have unexpectedly shown cardiovascular and renal benefit in clinical trials and in rodent models of nephropathy in obese and type 2 diabetic animals: Those drugs that target glucose transporters, such as the sodium glucose cotransporter 2 (SGLT2) inhibitors, empagliflozin and canagliflozin, slow renal decline, independent of their effects on glycemia. 76 –79 A recent study investigating possible mechanisms of renoprotection showed that SGLT2 inhibitors decrease TSP1 expression in two human proximal tubular cell lines. 80…”

Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction

“…We have previously shown that (1) engagement of RAGE with glycer-AGEs evokes inflammatory, thrombogenic, and fibrotic reactions in human renal proximal tubular cells via ROS generation, (2) sodium-glucose cotransporter 2 (SGLT2)-mediated, high glucose-induced ROS generation augments the glycer-AGE-induced apoptotic cell death of proximal tubular cells via RAGE induction, and (3) inhibitors of SGLT2, such as empagliflozin and tofogliflozin, protect against proximal tubular injury in diabetic animals through its anti-oxidative, anti-inflammatory and anti-fibrotic properties via inhibition of the glycer-AGE-RAGE axis [6,[13][14][15][16]. Furthermore, recently, high glucose or AGEs have been shown to promote human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition via oxidative stress generation, all of which were ameliorated by empagliflozin [17].…”