Metabolic Derangement in Polycystic Kidney Disease Mouse Models Is Ameliorated by Mitochondrial-Targeted Antioxidants

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.

Inhibition of Centrosome Clustering Reduces Cystogenesis and Improves Kidney Function in Autosomal Dominant Polycystic Kidney Disease

“…Overall, this mouse model effectively mimics the pathophysiological features of slow-onset progressive cystogenesis of human ADPKD, provides a large window of time to study the disease progression, and has been used extensively for preclinical testing of potential therapeutic compounds (26,(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42).…”