Abstract
Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1β) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity.
Highlights
Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients
This study has investigated the regulation of cisplatin-induced nephrotoxicity by microRNAs systematically
We first showed that cisplatin induced similar kidney injury and renal functional loss in PT-Dicer knock-out mice and wild-type mice, suggesting that overall depletion of microRNAs from proximal tubules does not have significant effects on cisplatin nephrotoxicity
Summary
Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. One upregulated miRNA was miR-375, whose expression was induced in cisplatin-treated renal tubular cells. We further demonstrated that HNF-1 protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-B collaboratively induce miR-375. MARCH 17, 2017 VOLUME 292 NUMBER 11 expression, which, in turn, represses HNF-1 activity, resulting in renal tubular cell apoptosis and nephrotoxicity. In 2010, we [16] demonstrated the induction of miR-34a during cisplatin treatment of mice in vivo and cultured renal tubular cells in vitro, revealing the first evidence of microRNA regulation in cisplatin nephrotoxicity.
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