Regulation Networks of Non-Coding RNA-Associated ceRNAs in Cisplatin-Induced Acute Kidney Injury

Abstract

Cisplatin is widely used as a chemotherapeutic drug to treat various solid tumors. However, it often induces severe side effects, including nephrotoxicity, which limits its application in clinical settings. Furthermore, the underlying mechanisms of action are unclear. Here, we applied whole-transcriptome RNA sequencing to a cisplatin-induced acute kidney injury (CP-AKI) mouse model to evaluate competing endogenous RNA (ceRNA) networks. We found 4460 mRNAs, 1851 long non-coding RNAs, 101 circular RNAs, and 102 microRNAs significantly differentially expressed between CP-AKI and control mice. We performed gene set enrichment analysis to reveal the biological functions of the mRNAs and constructed non-coding RNA-associated ceRNA networks in CP-AKI mice. Two ceRNA regulatory pathways, Lhx1os-203/mmu-miR-21a-3p/Slc7a13 and circular RNA_3907/mmu-miR-185-3p/Ptprn, were validated using quantitative real-time PCR. The protein–protein interaction network indicated that Il6, Cxcl1, Cxcl2, and Plk1 serve as hub genes and are highly connected with the inflammatory response or DNA damage. Transcription factors, such as Stat3, Cebpb, and Foxm1, regulate gene expression levels in CP-AKI. Our study provides insight into non-coding RNA-associated ceRNA networks and mRNAs in CP-AKI and identifies potential treatment targets.

Targeting polo‐like kinase 1 to treat kidney diseases

“…38 It is proposed that in AKI, Plk1 inactivates NOTCH1 as it acts as a substrate for hairy/ enhancer-of-split related with YRPW motif 1 and hairy and enhancer of Split 1 (HEY1/HES1), which are NOTCH targets and are associated with Plk1-linked DNA deterioration, resulting in cellular necrosis. 39 Furthermore, NOTCH signaling acts in two phases; the first is the reduced NOTCH1 expression, and the second phase entails developing resistance to the downregulation of NOTCH1. The continued expression of NOTCH1 helps to maintain metabolic activities that enhance the protection of cells against oxidative stress (Figure 3).…”

“…A study has revealed that in the cisplatin‐induced AKI rats, Plk1 overexpression, along with other cyclin‐dependent protein kinases, correlated with DNA damage 38 . It is proposed that in AKI, Plk1 inactivates NOTCH1 as it acts as a substrate for hairy/enhancer‐of‐split related with YRPW motif 1 and hairy and enhancer of Split 1 (HEY1/HES1), which are NOTCH targets and are associated with Plk1‐linked DNA deterioration, resulting in cellular necrosis 39 . Furthermore, NOTCH signaling acts in two phases; the first is the reduced NOTCH1 expression, and the second phase entails developing resistance to the downregulation of NOTCH1.…”

FOXM1: Functional Roles of FOXM1 in Non-Malignant Diseases

“…FOXM1 plays a role in renal tubule repair after acute renal injury. The transcription factor FOXM1 regulates gene expression levels in the AKI model [91]. The expression of FOXM1 increased after renal ischemia-reperfusion in mice.…”