Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants

Nastaran Daneshgar; Andrew W Baguley; Peir-In Liang; Wu Fei; Yi Chu; Michael T Kinter; Gloria A Benavides; Michelle S Johnson; Victor Darley-Usmar; Jianhua Zhang; Kung-Sik Chan; Dao-Fu Dai

doi:10.1038/s42003-021-02730-w

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Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants

Journal article

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Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants

Nastaran Daneshgar, Andrew W Baguley, Peir-In Liang, Wu Fei, Yi Chu, Michael T Kinter, Gloria A Benavides, Michelle S Johnson, Victor Darley-Usmar, Jianhua Zhang, …

Communications biology, Vol.4(1), 1200

01/01/2021

DOI: 10.1038/s42003-021-02730-w

PMCID: PMC8528863

PMID: 34671066

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1RC/null and PKD1RC/RC. Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD. Daneshgar et al. investigated the role of mitochondrial dysfunction in ADPKD and mitochondria protective agents as potential therapeutics. The authors reported decreased mitochondrial complex activity and downregulation of mitochondrial and metabolic proteins in ADPKD, and proposed mCAT overexpression or SS31 treatment to slow cystogenesis.

Animal Models

Antioxidants

Kidney Diseases

Metabolism

Mutation

Oxidative Stress

Phosphorylation

Proteomics

Catalase

Cysts

Extracellular signal-regulated kinase

Kidneys

Mitochondria

Polycystic kidney

Proteins

Tricarboxylic acid cycle

Details

Title: Subtitle: Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants
Creators: Nastaran Daneshgar
Andrew W Baguley
Peir-In Liang
Wu Fei
Yi Chu
Michael T Kinter
Gloria A Benavides
Michelle S Johnson
Victor Darley-Usmar
Jianhua Zhang - University of Alabama at Birmingham
Kung-Sik Chan
Dao-Fu Dai
Resource Type: Journal article
Publication Details: Communications biology, Vol.4(1), 1200
DOI: 10.1038/s42003-021-02730-w
PMID: 34671066
PMCID: PMC8528863
NLM abbreviation: Commun Biol
eISSN: 2399-3642
Publisher: Nature Publishing Group
Grant note: DOI: 10.13039/100000050, name: U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute, award: K08 HL145138-02
Language: English
Date published: 01/01/2021
Academic Unit: Statistics and Actuarial Science; Radiology; Pathology; Iowa Neuroscience Institute; Radiation Oncology; Internal Medicine
Record Identifier: 9984186626702771

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