Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

Abstract

Background/Aims: Cisplatin-induced acute kidney injury (AKI) involves damage to tubular cells via excess reactive oxygen species (ROS) generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived conditioned medium (CM) against cisplatin-induced AKI. Methods: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. Results: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data showed that the tubular β-catenin level was lower in AKI patients experiencing partial recovery than in patients experiencing complete recovery. Conclusion: The activation of the wnt/β-catenin pathway by CM protects against cisplatin-induced kidney injury, resulting in reduced apoptosis and intracellular ROS levels.

Berberine Exerts a Protective Effect on Gut-Vascular Barrier via the Modulation of the Wnt/Beta-Catenin Signaling Pathway During Sepsis

“…In addition, berberine reduces circulating microparticles, inhibits apoptosis of leukocyte-mediated endothelium [14], activates peroxisome proliferator-activated receptor gamma (PPARγ) and suppresses oxidative stress [15,16], ameliorates vascular permeability and increases tight junction by the upregulation of claudins (e.g., claudin-5) [17]. In the present study we aimed to investigate whether berberine might protect GVB via the modulation of the Wnt/beta-catenin signaling pathway, which can be blocked by inhibitor ICG001 both in vivo and vitro experiments [18][19][20][21].…”

CARsomes inhibit airway allergic inflammation in mice by inducing antigen‐specific Th2 cell apoptosis

“…The cells were cultured in the presence of CARsomes for 24 hours with cisplatin to test their responsiveness to apoptosis inducer. We observed that exposure to cisplatin (a nonspecific apoptosis inducer 13 expression is a specific feature of Ag-specific T-cell activation. 12 The results demonstrate that CARsomes can specifically induce Agspecific Th2 cell apoptosis.…”

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

“…7 show that b-catenin and cyclin D1 levels were decreased in HepG2SF1 and Huh7SF1 cells compared to their parental cells, while they were increased in AMPKtransfected cells. It has been demonstrated that b-catenin, through repression of the transcription factor TCF7L2, upregulates the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a), which has been shown to be involved in hepatocyte differentiation (Jiao et al, 2017;Wanet et al, 2017). In contrast, AMPK can directly phosphorylate and activate PGC-1a and regulate its expression (Colombo and Moncada, 2009).…”