Abstract
MicroRNAs are small noncoding RNAs that are produced endogenously and have emerged as important regulators in pathophysiological conditions such as development and tumorigenesis. Very little is known about the regulation of microRNAs in renal diseases, including acute kidney injury (AKI). In this study, we examined the regulation of microRNA-34a (miR-34a) in experimental models of cisplatin-induced AKI and nephrotoxicity. By Northern blot and real-time polymerase chain reaction analyses, we detected an induction of miR-34a in vitro during cisplatin treatment of mouse proximal tubular cells and also in vivo during cisplatin nephrotoxicity in C57BL/6 mice. In cultured cells, miR-34a was induced within a few hours. In mice, miR-34a induction was detectable in renal tissues after 1 d of cisplatin treatment and increased to approximately four-fold of control at d 3. During cisplatin treatment, p53 was activated. Inhibition of p53 with pifithrin-α abrogated the induction of miR-34a during cisplatin treatment of proximal tubular cells. In vivo, miR-34a induction by cisplatin was abrogated in p53-deficient mice, a result that further confirms a role for p53 in miR-34a induction during cisplatin nephrotoxicity. Functionally, antagonism of miR-34a with specific antisense oligonucleotides increased cell death during cisplatin treatment. Collectively, the results suggest that miR-34a is induced via p53 during cisplatin nephrotoxicity and may play a cytoprotective role for cell survival.
Highlights
Cisplatin, one of the most potent chemotherapy drugs, is a welldocumented nephrotoxin that induces acute kidney injury (AKI) in cancer patients
Because p53 is activated during cisplatin nephrotoxicity and contributes to renal cell injury and death, we investigated miR-34a expression and its role in relevant experimental models
We showed that miR-34a is induced during cisplatin treatment of renal proximal tubular cells in vitro and mice in vivo and that miR-34a induction under these experimental conditions is p53 dependent
Summary
One of the most potent chemotherapy drugs, is a welldocumented nephrotoxin that induces acute kidney injury (AKI) in cancer patients. Cisplatin accumulates in renal tubular cells, resulting in cell injury and death, contributing to the development of AKI (see [1,2] for reviews). Research during the last few years has identified several important signaling pathways that lead to tubular-cell apoptosis during cisplatin nephrotoxicity, including mitogen-activated protein kinase, p53 and others [3,4,5,6,7,8,9,10,11,12,13,14]. Our recent work has further demonstrated a DNA damage response mediated by ATR-Chk in p53 activation and tubular cell apoptosis during cisplatin nephrotoxicity [19]. P21, a cellcycle regulator with antiapoptotic activity, is induced during cisplatin nephrotoxicity via both p53-dependent and
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