Figure 4

Effects of ipragliflozin on oxidative stress in db/db mice. (a) High-dose ipragliflozin reduced the urinary excretion of 8-OHdG in db/db mice. (b,c) Immunostaining of 3-nitrotyrosine and the quantification of positive tubules showed that the ipragliflozin treatment reduced its expression in tubular epithelia in db/db mice. Arrowheads indicate nitrotyrosine-positive tubules. (d) High- and low-dose ipragliflozin prevented the up-regulation of Nox4; however, no significant differences were observed in the mRNA expression of heme oxygenase-1 (HO-1), catalase, or superoxide dismutase-1 (SOD1) or −2 (SOD2) in the kidneys of db/db mice. (e) Transmission electron microscopy of tubular epithelia showed that the mitochondria of db/db mice contained peripherally-located short cristae and were replaced by a homogenized matrix, which was ameliorated by the ipragliflozin treatment. Lower panels are high magnification pictures of the small squares in the upper panels. Data show the means ± SD, *p < 0.05 vs db/db (−), ^#p < 0.05 vs db/db-LD, ^†p < 0.05 vs db/db-HD, Bar = 50 μm in (b) and 1 μm in (e upper). n = 4–5 mice in each group, one-way ANOVA, Tukey’s multiple comparison.