4-Octyl itaconate attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.
Ren Fail
; 46(2): 2403653, 2024 Dec.
Article
in En
| MEDLINE
| ID: mdl-39291665
ABSTRACT
Objectives:
The aim of this study was to investigate the mechanism of itaconate's potential effect in diabetic kidney disease.Methods:
Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy.Results:
Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions.Conclusions:
4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Succinates
/
Organelle Biogenesis
/
Mice, Knockout
/
Diabetes Mellitus, Experimental
/
Diabetic Nephropathies
/
NF-E2-Related Factor 2
/
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Ren Fail
Journal subject:
NEFROLOGIA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
United kingdom