MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Abstract

Edited by Joel GottesfeldNephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatininduced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatininduced 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 upregulated 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-B attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-B in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1␤) as a key downstream target of miR-375. Of note, 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 expression, which, in turn, represses HNF-1␤ activity, resulting in renal tubular cell apoptosis and nephrotoxicity.

MicroRNA-668 represses MTP18 to preserve mitochondrial dynamics in ischemic acute kidney injury

“…In the luciferase microRNA target reporter assay, miR-668 showed a moderate (25%) effect on MTP18 3′-UTR sequence ( Figure 7F). Similarly, luciferase assay detected about 30% inhibition by miR-375 on its target HNF-1β sequence in our recent study (58). The luciferase assay may be affected by multiple factors such as the transfection and expression efficiency of the microRNAs and luciferase constructs, and the 3D RNA structure of 3′-UTR due to the DNA sequence chosen to insert into the luciferase construct (59,60).…”

The negative feedback loop of NF-κB/miR-376b/NFKBIZ in septic acute kidney injury

“…These results verified LPS-induced NF-κB activation in renal tubular cells. To determine the involvement of NF-κB in LPS-induced downregulation of miR-376b, we tested the effect of TPCA-1, a specific IKK inhibitor that prevents NF-κB activation by blocking IκB phosphorylation and dissociation from NF-κB ( 30 ). As shown in Figure 3D , TPCA-1 prevented an miR-376b decrease during LPS treatment of BUMPT cells.…”

Discovery and validation of miR-452 as an effective biomarker for acute kidney injury in sepsis

“…The cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS). For LPS treatment, BUMPT cells at a 50-60% confluency were maintained in DMEM medium containing 0.2% FBS for 24 h. The cells were then changed to DMEM medium containing 0.2% FBS plus 10 μg/mL LPS for another 8 h. For TPCA-1 treatment, TPCA-1 was added concurrently with LPS at the final concentration of 100 μM 31 .…”