Comprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-03-05

AUTHORS

Michitsugu Kamezaki, Tetsuro Kusaba, Kazumi Komaki, Yohei Fushimura, Noriko Watanabe, Kisho Ikeda, Takashi Kitani, Noriyuki Yamashita, Masahiro Uehara, Yuhei Kirita, Yayoi Shiotsu, Ryosuke Sakai, Takuya Fukuda, Masahiro Yamazaki, Michiaki Fukui, Satoaki Matoba, Keiichi Tamagaki

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. More... »

PAGES

4029

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-22229-5

DOI

http://dx.doi.org/10.1038/s41598-018-22229-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1101244869

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29507299


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17 schema:description 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.
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23 schema:keywords NADPH oxidase 4 expression
24 SGLT2
25 SGLT2i
26 abnormal hemodynamics
27 addition
28 albumin excretion
29 analysis
30 blood glucose levels
31 conclusion
32 cortex
33 cortical hypoxia
34 development
35 diabetic kidney disease
36 diabetic kidney disease progression
37 diabetic mice
38 diabetic nephropathy
39 differences
40 different doses
41 disease
42 disease progression
43 dose-dependent differences
44 doses
45 early diabetic nephropathy
46 effect
47 effect of ipragliflozin
48 epithelium
49 excretion
50 experimental study
51 expression
52 glomerular hypertrophy
53 glomerular phenotype
54 glomerular podocytes
55 glucose
56 glucose levels
57 hemodynamics
58 hypertrophy
59 hypoxia
60 inhibitors
61 integrity
62 ipragliflozin
63 ipragliflozin treatment
64 isolation
65 kidney cortex
66 kidney disease
67 kidney disease progression
68 levels
69 mechanism
70 mice
71 molecular mechanisms
72 nephropathy
73 order
74 oxidase 4 expression
75 oxidative stress
76 oxygen tension
77 pharmacological effects
78 phenotype
79 podocyte integrity
80 podocytes
81 prevention
82 progression
83 renal cortical hypoxia
84 renal tissue hypoxia
85 renoprotective effects
86 sodium glucose
87 stress
88 study
89 subsequent oxidative stress
90 tension
91 tissue hypoxia
92 treatment
93 tubular epithelium
94 urinary albumin excretion
95 vivo
96 weeks
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