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Pregnane X Receptor (PXR) protects against cisplatin-induced acute kidney injury

ABSTRACT: Background: Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many nonxenobiotic functions including the regulation of cell proliferation, inflammatory response and glucose and lipid metabolism. Methods: In this study, we aimed to investigate the role of PXR in cisplatin-induced nephrotoxicity. CAKI model was performed in wild-type or PXR knockout mice. Pregnenolone 16α-carbonitrile (PCN), a mouse PXR specific agonist, was used for PXR activation. The renal function, biochemical, histopathological and molecular alterations were examined in mouse blood, urine or renal tissues. Whole transcriptome analysis was performed by RNA sequencing. Dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were applied to determine the regulation of PXR on its target genes. Results: We found that PXR activation significantly attenuated CAKI as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative and endoplasmic reticulum stress, and suppressed inflammatory factor expression. RNA sequencing analysis revealed that the renoprotective effect of PXR was associated with multiple crucial signaling pathways. In particular, PXR protected against cisplatin-induced AKI by the activation of PI3K/AKT pathway and the induction of multidrug and toxin extrusion 1 (MATE1), an important transporter mediating cellular excretion of cisplatin, in the kidney. Conclusions: Our results demonstrate that PXR activation can preserve renal function in cisplatin-induced AKI and suggest a possibility of PXR as a novel therapeutic target for cisplatin-induced nephrotoxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE147256 | GEO | 2023/03/20

REPOSITORIES: GEO

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Project description:Acute kidney injury (AKI) is characterized by a rapid reduction in renal function and glomerular filtration rate (GFR). The broadly used anti-cancer chemotherapeutic agent cisplatin often induces AKI as an adverse drug side effect. Therapies targeted at the reversal of AKI and its potential progression to chronic kidney disease or end-stage renal disease are currently insufficiently effective. Mesenchymal stromal cells (MSC) possess diverse immunomodulatory properties that confer upon them significant therapeutic potential for the treatment of diverse inflammatory disorders. Human dermal MSCs expressing ATP-Binding Cassette member B5 (ABCB5) have shown therapeutic efficacy in clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. In preclinical studies, ABCB5+ MSCs have also been shown to reverse metabolic reprogramming in polycystic kidney cells, suggesting a capacity for this cell subset to also improve organ function in kidney diseases. Here, we aimed to explore the therapeutic capacity of ABCB5+ MSCs to improve renal function in a preclinical rat model of cisplatin-induced AKI. First, ABCB5+ MSCs suppressed cisplatin-induced apoptosis of human conditionally-immortalized proximal tubular epithelial cells in vitro. Second, ABCB5+ MSCs inhibited the proliferation of either human or rat peripheral blood mononuclear cells. Third, ABCB5+ MSCs decreased TNF-α secretion after LPS stimulation in both human and rat macrophages. Fourth, clinical-grade ABCB5+ MSCs grafted intravenously and intraperitoneally to a cisplatin-induced AKI murine model exerted modulatory effects on mRNA expression patterns towards an anti-inflammatory and pro-regenerative state despite an apparent lack of amelioration of renal damage at physiologic, metabolic, and histologic levels. Our results demonstrate anti-inflammatory and pro-regenerative effects of clinical grade ABCB5+ MSCs in vitro and in vivo and suggest potential therapeutic utility of this cell population for treatment or prevention of cisplatin chemotherapy-induced tissue toxicity.

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Pregnane X Receptor (PXR) protects against cisplatin-induced acute kidney injury

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