p53 activates miR-192-5p to mediate vancomycin induced AKI

Abstract

Pathogenic role of p53 in AKI remains controversial and the underlying mechanism is unclear. Here, we tested whether the inhibition of p53 may ameliorate vancomycin (VAN) induced acute kidney injury (AKI). Mice with p53 knock out (p53-KO) were resistant to VAN induced AKI, indicated by the analysis of renal function, histology, and apoptosis. Mechanistically, AKI was associated with the upregulation of several known p53 target genes, including Bax and p21, and this association was attenuated in p53-KO mice. Furthermore, the expression of miR-192-5p was significantly decreased in the p53-KO kidney tissues. In human renal tubular epithelial cell line (HK-2), VAN induced p53 accumulation and miR-192-5p expression. Both apoptosis of HK-2 cells and expression of miR-192-5p were also suppressed by pifithrin-α. Anti-miR-192-5p significantly blocked VAN-induced apoptosis and caspase activity in HK-2 cells. Consistently, in vivo inhibition of miR-192-5p also suppressed VAN induced AKI. Thus, we provided clinical and genetic evidence that p53 was associated with the development of VAN induced AKI through upregulation of miR-192-5p.

Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC‐δ

“…The animal experiments were performed according to the rules approved by the animal ethics committee from Central South University. The HK-2 cells were as previously described (12,13).…”

FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury

“…Relevant to the present study, serum FGF21 has been shown to increase in patients with CKD (30). Moreover, P53 has been implicated in renal fibrosis and apoptosis in experimental models, such as the urinary obstruction model (38). Thus, it is possible FGF21 may also be induced to alleviate chronic renal pathology induced by multiple low doses of cisplatin through P53.…”

Vancomycin‐Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention

“…In VIKI, MBD2 binds to the methylated CpG elements of miR‐301a‐5p promoter and activates the promoter, thus increasing transcription of miR‐301a‐5p, which upregulates p53, caspase activity, and vancomycin‐induced apoptosis in HK‐2 cells. Additionally, p53 has been shown to induce apoptosis via miR‐192‐5p in wild‐type mice, which was suppressed in p53‐KO mice 86 . Blocking miR‐301a‐5p 85 or inhibiting miR‐192‐5p 86 with respective antisense oligonucleotides ameliorated VIKI in C57BL/6 mice.…”

“…Additionally, p53 has been shown to induce apoptosis via miR‐192‐5p in wild‐type mice, which was suppressed in p53‐KO mice 86 . Blocking miR‐301a‐5p 85 or inhibiting miR‐192‐5p 86 with respective antisense oligonucleotides ameliorated VIKI in C57BL/6 mice.…”

“…The miRNA appears to be an important part of this VIKI mechanistic pathway. The miRNAs miR‐301a‐5p and miR‐192‐5p have been implicated in the development of VIKI through methyl‐CpG‐binding domain protein 2 (MBD2) and p53 85, 86 . Methyl‐CpG‐binding domain proteins, are protein readers of methylation and are actively involved in DNA‐methylation‐mediated transcriptional regulation by binding to methylated CpG on the DNA and either blocking other protein factors from binding to DNA or by binding to promoters of actively transcribed genes 87 .…”