2. Academic Validation
  3. 4-Octyl itaconate attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis

4-Octyl itaconate attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis

  • Ren Fail. 2024 Dec;46(2):2403653. doi: 10.1080/0886022X.2024.2403653.
Muqing Shao 1 2,  Jiayao Chen 2 3,  Fuwei Zhang 2 4,  Qian Su 1 2,  Xiaoqian Lin 2 3,  Weiwei Wang 2 4,  Caiyu Chen 5,  Hongmei Ren 5,  Shuo Zheng 5,  Suocheng Hui 2 3,  Si Qin 1,  Yinxing Ni 1,  Jian Zhong 1,  Jian Yang 2 3
Affiliations

Affiliations

  • 1 Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
PMID: 39291665 DOI: 10.1080/0886022X.2024.2403653
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.

Keywords

4-octyl itaconate; Diabetic kidney disease; Nrf2; immune responsive gene 1; mitochondrial biogenesis; renal tubular injury.

Figures
Products