Comprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice

Abstract

Clinical and experimental studies have shown that sodium glucose co-transporter 2 inhibitors (SGLT2i) contribute to the prevention of diabetic kidney disease progression. In order to clarify its pharmacological effects on the molecular mechanisms underlying the development of diabetic kidney disease, we administered different doses of the SGLT2i, ipragliflozin, to type 2 diabetic mice. A high-dose ipragliflozin treatment for 8 weeks lowered blood glucose levels and reduced urinary albumin excretion. High- and low-dose ipragliflozin both inhibited renal and glomerular hypertrophy, and reduced NADPH oxidase 4 expression and subsequent oxidative stress. Analysis of glomerular phenotypes using glomeruli isolation demonstrated that ipragliflozin preserved podocyte integrity and reduced oxidative stress. Regarding renal tissue hypoxia, a short-term ipragliflozin treatment improved oxygen tension in the kidney cortex, in which SGLT2 is predominantly expressed. We then administered ipragliflozin to type 1 diabetic mice and found that high- and low-dose ipragliflozin both reduced urinary albumin excretion. In conclusion, we confirmed dose-dependent differences in the effects of ipragliflozin on early diabetic nephropathy in vivo. Even low-dose ipragliflozin reduced renal cortical hypoxia and abnormal hemodynamics in early diabetic nephropathy. In addition to these effects, high-dose ipragliflozin exerted renoprotective effects by reducing oxidative stress in tubular epithelia and glomerular podocytes.

Long-Term Effects of Ipragliflozin on Diabetic Nephropathy and Blood Pressure in Patients With Type 2 Diabetes: 104-Week Follow-up of an Open-Label Study

“…Furthermore, Kamezaki et al recently reported that even low-dose ipragliflozin, given to type 2 diabetic mice, reduced renal cortical hypoxia and abnormal hemodynamics in early diabetic nephropathy. In addition to these effects, high-dose ipragliflozin exerted renoprotective effects by reducing oxidative stress in tubular epithelia and glomerular podocytes [ 20 ]. These prior studies demonstrated that SGLT2 inhibitors exert renoprotective effects by having beneficial effects not only on glycemic control, glomerular hyperfiltration, blood pressure, and body weight reduction, but also through multifactorial mechanisms.…”

Effects of ipragliflozin on glycemic control, appetite and its related hormones: A prospective, multicenter, open‐label study (SOAR‐KOBE Study)

“…Inhibitors of sodium–glucose cotransporter 2 (SGLT‐2) promote urinary glucose excretion by selectively blocking SGLT‐2 activity in proximal tubules of the kidney. SGLT‐2 inhibitors thus ameliorate hyperglycemia, dyslipidemia and insulin resistance; reduce bodyweight; and attenuate β‐cell exhaustion. However, several clinical trials have shown that the effect of these agents on bodyweight is smaller than would be expected from the increase in urinary glucose excretion.…”

Effects of ipragliflozin on the development and progression of kidney disease in patients with type 2 diabetes: An analysis from a multicenter prospective intervention study

“…Kidokoro et al 29 also reported that empagliflozin increased urinary adenosine excretion and reduced hyperfiltration through afferent arteriolar constriction, effects that were abolished by A1 adenosine receptor blockade in mice. In addition, ipragliflozin has been reported to suppress renal and glomerular hypertrophy, and reduce nicotinamide adenine dinucleotide phosphate oxidase 4 expression and subsequent oxidative stress in mice 30 . The fact that eGFR levels were maintained without decreasing in the eGFR <60 group in the present study suggests that this renoprotective effect confirmed in animal experiments might also occur in humans.…”