Complement component C5a induces aberrant epigenetic modifications in renal tubular epithelial cells accelerating senescence by Wnt4/βcatenin signaling after ischemia/reperfusion injury

Giuseppe Castellano, Rossana Franzin, Fabio Sallustio, Alessandra Stasi, Barbara Banelli, Massimo Romani, Giuseppe De Palma, Giuseppe Lucarelli, Chiara Divella, Michele Battaglia, Antonio Crovace, Francesco Staffieri, Giuseppe Grandaliano, Giovanni Stallone, Pasquale Ditonno, Paolo Cravedi, Vincenzo Cantaluppi, Loreto Gesualdo

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Epigenetic mechanisms, such as DNA methylation, affect tubular maladaptive response after Acute Kidney Injury (AKI) and accelerate renal aging. Upon ischemia/reperfusion (I/R) injury, Complement activation leads to C5a release that mediates damage; however, little is known about the effect of C5a-C5a Receptor (C5aR) interaction in Renal Tubular Epithelial Cells (RTEC). Through a whole-genome DNA methylation analysis in cultured RTEC, we found that C5a induced aberrant methylation, particularly in regions involved in cell cycle control, DNA damage and Wnt signaling. The most represented genes were BCL9, CYP1B1 and CDK6. C5a stimulation of RTEC led to up-regulation of SA-β Gal and cell cycle arrest markers such as p53 and p21. C5a increased also IL-6, MCP-1 and CTGF gene expression, consistent with SASP development. In accordance, in a swine model of renal I/R injury, we found the increased expression of Wnt4 and βcatenin correlating with SA-β Gal, p21, p16 and IL-6 positivity. Administration of Complement Inhibitor (C1-Inh), antagonized SASP by reducing SA-β Gal, p21, p16, IL-6 and abrogating Wnt4/βcatenin activation. Thus, C5a affects the DNA methylation of genes involved in tubular senescence. Targeting epigenetic programs and Complement may offer novels strategies to protect tubular cells from accelerated aging and to counteract progression to Chronic Kidney Disease.

Original languageEnglish
Pages (from-to)4382-4406
Number of pages25
JournalAging
Volume11
Issue number13
DOIs
StatePublished - 1 Jul 2019

Keywords

  • Acute kidney injury
  • Complement cascade
  • DNA methylation
  • Renal Inflammaging

Fingerprint

Dive into the research topics of 'Complement component C5a induces aberrant epigenetic modifications in renal tubular epithelial cells accelerating senescence by Wnt4/βcatenin signaling after ischemia/reperfusion injury'. Together they form a unique fingerprint.

Cite this