Conditioned medium from Adipose Stromal Cells reduces cisplatin-induced proximal tubular epithelial cell apoptosis via downregulation of miR-181a-5p

Cisplatin is one of the most commonly used and most potent chemotherapy drugs against a variety of solid tumours. However, side effects in noncancer tissues, especially kidney nephrotoxicity, limit its use. Several studies have highlighted the therapeutic potential of Mesenchymal Stromal Cells (MSCs) in renal disorders through the release of cytokines, growth factors and extracellular vesicles. We postulate that part of the protective activity of MSC-conditioned medium occurs via the modulation of miRNA expression in injured renal cells, followed by miRNA-mediated posttranscriptional gene regulation. Conditionally immortalised proximal tubule epithelial cells (ciPTECs) were treated with cisplatin for 24 hours to mimic renal injury. MSC-mediated protection was mimicked by adding Adipose Stromal Cells (ASC)-derived conditioned medium (ASC-CM) 1 hour after cisplatin treatment for a period of 23 hours. Cellular apoptosis and p53 levels were analysed, and small-RNA sequencing was performed to address cisplatin-mediated changes and the postulated protective effects of ASC-CM. Cisplatin-treated ciPTECs presented increased p53 protein levels and cell apoptosis. ASC-CM reduced cisplatin-induced cellular toxicity and protected against apoptosis. Differential expression analysis of small RNAs in treated ciPTECs revealed that miR-181a-5p is modulated by ASC-CM in the context of cisplatin-mediated injury. miR-181a-5p is known to play a role in apoptosis. Functional assays through downregulation or upregulation of this miRNA coupled with apoptosis assessment demonstrated its involvement in the protective role of ASC-CM within this in vitro renal injury system. Conclusion: ASC-CM reduces p53 expression and apoptosis induced by the cytotoxic action of cisplatin through the downregulation of miR-181a-5p.