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

Giuseppe Grandaliano, 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, Giovanni Stallone, Pasquale Ditonno, Paolo Cravedi, Vincenzo Cantaluppi, Loreto Gesualdo

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

16 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)4382-4406
Numero di pagine25
RivistaAging
Volume11
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

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

Fingerprint Entra nei temi di ricerca di 'Complement component C5a induces aberrant epigenetic modifications in renal tubular epithelial cells accelerating senescence by Wnt4/βcatenin signaling after ischemia/reperfusion injury'. Insieme formano una fingerprint unica.

Cita questo