Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1

Abstract

Mesenchymal stem cells (MSC) could be a candidate for cell-based therapy in chronic kidney disease (CKD); however, the uremic toxin in patients with CKD restricts the therapeutic efficacy of MSCs. To address this problem, we explored the effect of pioglitazone as a measure against exposure to the uremic toxin P-cresol (PC) in MSCs. Under PC exposure conditions, apoptosis of MSCs was induced, as well as PC-induced dysfunction of mitochondria by augmentation of mitofusion, reduction of mitophagy, and inactivation of mitochondrial complexes I and IV. Treatment of MSCs with pioglitazone significantly inhibited PC-induced apoptosis. Pioglitazone also prevented PC-induced mitofusion and increased mitophagy against PC exposure through up-regulation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK-1). Furthermore, pioglitazone protected against PC-induced mitochondrial dysfunction by increasing the cytochrome c oxidase subunit 4 (COX4) level and activating complexes I and IV, resulting in enhancement of proliferation. In particular, activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) regulated the pioglitazone-mediated up-regulation of PINK-1. These results indicate that pioglitazone protects MSCs against PC-induced accumulated mitochondrial dysfunction via the NF-κB–PINK-1 axis under P-cresol exposure conditions. Our study suggests that pioglitazone-treated MSCs could be a candidate for MSC-based therapy in patients with CKD.

Effects of p-Cresol on Senescence, Survival, Inflammation, and Odontoblast Differentiation in Canine Dental Pulp Stem Cells

“…Moreover, damaged DNA produced from the nuclei of senescent cells may stimulate inflammatory pathways and finally lead to apoptosis. Our model shows that apoptosis-associated proteins are significantly expressed in PC-treated DPSCs, which is consistent with an earlier report [56].…”

“…Moreover, effective DPSCs-based therapy in aged patients should be enhanced; we recently used CCR3 antagonist to retreat the adverse effects of PC on periodontal ligament cells, resulting in enhanced pulp regeneration in aged dogs [29]. In addition, other substances such as fucoidan, pioglitazone, and melatonin showed protective effects against PC-induced cellular senescence in MSCs [28,56,62]. Taken together, substances and molecules that can restore regenerative DPSCs and reserve their physiology against PC-induced senescence should be used in aged individuals, especially those with uremia.…”

Melatonin‐stimulated exosomes enhance the regenerative potential of chronic kidney disease‐derived mesenchymal stem/stromal cells via cellular prion proteins

“…CKD induces the progressive loss of function in kidneys resulting in ineffective homeostasis in the body. CKD‐induced uremic toxins, such as indoxyl sulfate and p‐cresol, hamper the biological activities of MSCs and lead to cardiovascular disease, weakened bones, malfunctioning central nervous system, and improper inflammation in patients . The regenerative potential of CKD‐MSCs is also suppressed in a murine ischemic injury .…”

“…system, and improper inflammation in patients. 12,13 The regenerative potential of CKD-MSCs is also suppressed in a murine ischemic injury. 10,14 Consistent with these findings, our results have shown that biological functions like senescence, proliferation, and mitochondrial activity were significantly decreased in CKD-MSCs and treatment with MT exosomes drastically improved these CKD-mediated pathophysiological conditions.…”

Knockdown of CK2α reduces P-cresol-induced fibrosis in human renal proximal tubule epithelial cells via the downregulation of profilin-1

“…In CKD patients, the damaged kidney secretes uremic toxics such as indoxyl sulfate and P-cresol, and the accumulation of these toxins causes various complications. Our previous studies proved that P-cresol, a low molecular weight uremic toxin with high affinity to protein, reduced cellular functions by various mechanisms, including accumulated reactive oxygen species (ROS), cell senescence, abnormal mitochondria, and endoplasmic reticulum stress [4][5][6]. Therefore, in the treatment of CKD patients, it is important to protect renal proximal tubule epithelial cells against damages caused by uremic toxins.…”