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.
Keywords: cellular prion protein; chronic kidney disease; endoplasmic reticulum stress; mesenchymal stem cells; mitochondria; proliferator-activated receptor gamma coactivator 1-alpha.