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Published on: January 7, 2013
MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β
Jielu Hao1,2, Qiang Lou2,3, Qingqing Wei2
1From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
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.
Insights
Cisplatin chemotherapy causes kidney damage. This study reveals miR-375, induced by P53 and NF-κB, promotes this nephrotoxicity by suppressing protective HNF-1β. Understanding this pathway aids in developing kidney-protective strategies.
Area of Science:
- Molecular Biology
- Oncology
- Nephrology
Background:
- Cisplatin chemotherapy is vital for cancer treatment but causes significant kidney toxicity (nephrotoxicity).
- The exact mechanisms behind cisplatin-induced nephrotoxicity are not fully understood, hindering the development of effective protective therapies.
- MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are implicated in various cellular processes, including drug-induced toxicity.
Purpose of the Study:
- To investigate the role of specific microRNAs (miRNAs) in the development of cisplatin-induced nephrotoxicity.
- To identify key molecular players and pathways involved in cisplatin's damaging effects on kidney cells.
- To explore potential therapeutic targets for mitigating cisplatin-induced kidney damage.
Main Methods:
- Conditional knockout of the miRNA-generating enzyme Dicer in mouse kidney proximal tubular cells.
- Microarray analysis to profile miRNA expression in kidney cortical tissues after cisplatin treatment.
- In vitro experiments involving inhibition of specific miRNAs (miR-375) and key signaling molecules (P53, NF-κB) in renal tubular cells.
- Western blot analysis to assess protein levels of downstream targets (HNF-1β).
Main Results:
- Overall miRNA depletion did not alter cisplatin-induced nephrotoxicity.
- Microarray analysis identified 47 up-regulated and 20 down-regulated miRNAs in cisplatin-treated kidneys.
- miR-375 expression was significantly increased in cisplatin-treated renal cells and promoted apoptosis.
- P53 and NF-κB pathways were found to induce miR-375 expression.
- Hepatocyte nuclear factor 1 homeobox B (HNF-1β) was identified as a direct downstream target of miR-375, and its expression protected against cisplatin-induced apoptosis.
Conclusions:
- Cisplatin exposure triggers P53 and NF-κB to up-regulate miR-375.
- miR-375 promotes cisplatin-induced renal tubular cell apoptosis by suppressing the protective factor HNF-1β.
- These findings elucidate a novel molecular mechanism of cisplatin nephrotoxicity and highlight miR-375 and HNF-1β as potential targets for renoprotective strategies.
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