A CPEB2/ANGPTL3 feedback loop promotes the progression of podocyte injury in nephrotic syndrome

Podocyte injury is the primary pathology responsible for 70–90% of nephrotic syndrome (NS) in children, a condition closely associated with the aberrant expression of Angiopoietin-like-3 (ANGPTL3). The regulatory mechanism by which ANGPTL3 is upregulated during NS progression remains elusive. In this study, we found that ANGPTL3 can be regulated by Cytoplasmic polyadenylation element binding protein 2 (CPEB2) through translational control, and conversely, CPEB2 can be transcriptionally regulated in response to ANGPTL3 signaling as a feedback loop. Exposure to puromycin aminonucleoside (PAN) or adriamycin (ADR) dose-dependently increased the expression of both CPEB2 and ANGPTL3 in MPC-5 cells. Ectopic overexpression of CPEB2 in MPC-5 cells significantly promoted cell apoptosis and migration, which could be abrogated by knockdown of ANGPTL3. Mechanistically, the regulation of ANGPTL3 by CPEB2 was attributed to translational promotion. CPEB2 could directly bind the 3′ untranslated coding region (UTR) of ANGPTL3 mRNA, thereby promoting the recruitment of ANGPTL3 transcripts to the translation initiation complexes. Consequently, polysomal profiling suggested that the abundance of ANGPTL3 transcripts in actively high-translating polysomes was dramatically increased upon CPEB2 overexpression. On the other hand, ANGPTL3 signaling could increase the mRNA stability of CPEB2, thereby promoting the mRNA expression of CPEB2. Furthermore, the role of CPEB2/ANGPTL3 in podocyte injury was validated in vivo. Depletion of CPEB2 with adeno-associated virus (AAV9)-shCPEB2 significantly decreased the expression of ANGPTL3, and consequently mitigated albuminuria and histopathological injury in ADR-induced NS mice. In conclusion, this study highlighted the CPEB2/ANGPTL3 feedback loop as a novel mechanism contributing to the progression of podocyte injury.

• Publication year

  2025

• Venue

  Scientific Reports

• Publication date

  2025-11-11

• Fields of study

  Medicine

• Identifiers
  DOI 10.1038/s41598-025-23393-1PMID 41219382PMCID 12606126
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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