Abstract
Mesenchymal stem cells (MSCs) are optimal sources of autologous stem cells for cell-based therapy in chronic kidney disease (CKD). However, CKD-associated pathophysiological conditions, such as endoplasmic reticulum (ER) stress and oxidative stress, decrease MSC function. In this work, we study the protective effect of pioglitazone on MSCs isolated from CKD patients (CKD-MSCs) against CKD-induced ER stress. In CKD-MSCs, ER stress is found to induce mitochondrial reactive oxygen species generation and mitochondrial dysfunction. Treatment with pioglitazone reduces the expression of ER stress markers and mitochondrial fusion proteins. Pioglitazone increases the expression of cellular prion protein (PrPC) in CKD-MSCs, which is dependent on the expression levels of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Treatment with pioglitazone is found to protect CKD-MSCs against reactive oxygen species generation, aberrant mitochondrial oxidative phosphorylation of complexes I and IV, and aberrant proliferation capacity through the PGC-1α-PrPC axis. These results indicate that pioglitazone protects the mitochondria of MSCs from CKD-induced ER stress. Pioglitazone treatment of CKD-MSCs may be a potential therapeutic strategy for CKD patients.
Highlights
Chronic kidney disease (CKD) is a global health concern due to the increasing prevalence (8–16%) of the disease [1]
CKD-induced endoplasmic reticulum (ER) stress in human Mesenchymal stem cells (MSCs) was evaluated by measuring the expression levels of ER stress markers, protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2 alpha, activating transcription factor 4 (ATF4), inositol-requiring enzyme 1 alpha (IRE1a), c-Jun N-terminal kinase (JNK), and CCAAT-enhancer-binding proteins (C/EBP) homologous protein (CHOP)
A previous study reported that reactive oxygen species (ROS) generation is increased in CKD patients by uremic toxin [8]
Summary
Chronic kidney disease (CKD) is a global health concern due to the increasing prevalence (8–16%) of the disease [1]. Acute kidney injury (AKI) is defined as a kidney disease with rapid loss of renal function Both CKD and AKI are considered risk factors for the development of diseases that progress from AKI to CKD or CKD to AKI [2,3]. CKD is associated with several pathophysiological conditions, including type 1 or type 2 diabetes, high blood pressure, glomerulonephritis, interstitial nephritis, vesicoureteral reflux, and kidney infection. These conditions can impair kidney function for long periods of time [1,4,5]. These pathophysiological conditions are major hurdles for the clinical application of stem cell- and progenitor cell-based therapies
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