Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice.
Albuminuria
/ etiology
Animals
Biomarkers
Blood Glucose
Body Weight
Chymases
/ antagonists & inhibitors
Creatine
/ metabolism
Diabetes Mellitus, Experimental
Diabetic Nephropathies
/ diagnosis
Disease Models, Animal
Gene Expression
Immunohistochemistry
Malondialdehyde
/ metabolism
Mast Cells
/ metabolism
Mice
NADPH Oxidase 4
/ genetics
RNA, Messenger
Albuminuria
Chymase
Diabetes
Inhibitor
Kidney
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
11 Oct 2020
11 Oct 2020
Historique:
received:
25
09
2020
revised:
09
10
2020
accepted:
10
10
2020
entrez:
14
10
2020
pubmed:
15
10
2020
medline:
3
3
2021
Statut:
epublish
Résumé
Chymase has several functions, such as angiotensin II formation, which can promote diabetic kidney disease (DKD). In this study, we evaluated the effect of the chymase inhibitor TY-51469 on DKD in diabetic db/db mice. Diabetic mice were administered TY-51469 (10 mg/kg/day) or placebo for 4 weeks. No significant difference was observed in body weight and fasting blood glucose between TY-51469- and placebo-treated groups. However, a significant reduction in urinary albumin/creatinine ratio was observed in the TY-51469-treated group compared with the placebo-treated group. In the renal extract, chymase activity was significantly higher in placebo-treated mice than in non-diabetic db/m mice, but it was reduced by treatment with TY-51469. Both NADPH oxidase 4 expression and the oxidative stress marker malondialdehyde were significantly augmented in the placebo-treated group, but they were attenuated in the TY-51469-treated group. Significant increases of tumor necrosis factor-α and transforming growth factor-β mRNA levels in the placebo-treated group were significantly reduced by treatment with TY-51469. Furthermore, the expression of nephrin, which is a podocyte-specific protein, was significantly reduced in the placebo-treated group, but it was restored in the TY-51469-treated group. These findings demonstrated that chymase inhibition reduced albuminuria via attenuation of podocyte injury by oxidative stress.
Identifiants
pubmed: 33050674
pii: ijms21207495
doi: 10.3390/ijms21207495
pmc: PMC7589797
pii:
doi:
Substances chimiques
Biomarkers
0
Blood Glucose
0
RNA, Messenger
0
Malondialdehyde
4Y8F71G49Q
NADPH Oxidase 4
EC 1.6.3.-
Chymases
EC 3.4.21.39
Creatine
MU72812GK0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Voucher
ID : 6baa4bd9cb53c4b8
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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