PMID- 31284268 OWN - NLM STAT- MEDLINE DCOM- 20200721 LR - 20200721 IS - 1945-4589 (Electronic) IS - 1945-4589 (Linking) VI - 11 IP - 13 DP - 2019 Jul 8 TI - Complement component C5a induces aberrant epigenetic modifications in renal tubular epithelial cells accelerating senescence by Wnt4/betacatenin signaling after ischemia/reperfusion injury. PG - 4382-4406 LID - 10.18632/aging.102059 [doi] AB - 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-beta 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 betacatenin correlating with SA-beta Gal, p21, p16 and IL-6 positivity. Administration of Complement Inhibitor (C1-Inh), antagonized SASP by reducing SA-beta Gal, p21, p16, IL-6 and abrogating Wnt4/betacatenin 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. FAU - Castellano, Giuseppe AU - Castellano G AD - Nephrology, Dialysis and Transplantation Unit, University of Bari "Aldo Moro", Bari, Italy. FAU - Franzin, Rossana AU - Franzin R AD - Nephrology, Dialysis and Transplantation Unit, University of Bari "Aldo Moro", Bari, Italy. FAU - Sallustio, Fabio AU - Sallustio F AD - Nephrology, Dialysis and Transplantation Unit, University of Bari "Aldo Moro", Bari, Italy. AD - Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, Italy. FAU - Stasi, Alessandra AU - Stasi A AD - Nephrology, Dialysis and Transplantation Unit, University of Bari "Aldo Moro", Bari, Italy. FAU - Banelli, Barbara AU - Banelli B AD - IRCCS Ospedale Policlinico San Martino, Genova, Italy. FAU - Romani, Massimo AU - Romani M AD - IRCCS Ospedale Policlinico San Martino, Genova, Italy. FAU - De Palma, Giuseppe AU - De Palma G AD - Nephrology, Dialysis and Transplantation Unit, University of Bari "Aldo Moro", Bari, Italy. FAU - Lucarelli, Giuseppe AU - Lucarelli G AD - Urology, Andrology and Renal Transplantation Unit, University of Bari, Bari, Italy. FAU - Divella, Chiara AU - Divella C AD - Nephrology, Dialysis and Transplantation Unit, University of Bari "Aldo Moro", Bari, Italy. FAU - Battaglia, Michele AU - Battaglia M AD - Urology, Andrology and Renal Transplantation Unit, University of Bari, Bari, Italy. FAU - Crovace, Antonio AU - Crovace A AD - Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. FAU - Staffieri, Francesco AU - Staffieri F AD - Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. FAU - Grandaliano, Giuseppe AU - Grandaliano G AD - Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. FAU - Stallone, Giovanni AU - Stallone G AD - Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. FAU - Ditonno, Pasquale AU - Ditonno P AD - Urology, Andrology and Renal Transplantation Unit, University of Bari, Bari, Italy. FAU - Cravedi, Paolo AU - Cravedi P AD - Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Cantaluppi, Vincenzo AU - Cantaluppi V AD - Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Eastern Piedmont "A. Avogadro" (UPO), Novara, Italy. FAU - Gesualdo, Loreto AU - Gesualdo L AD - Nephrology, Dialysis and Transplantation Unit, University of Bari "Aldo Moro", Bari, Italy. LA - eng GR - R01 DK119431/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Aging (Albany NY) JT - Aging JID - 101508617 RN - 0 (BCL9 protein, human) RN - 0 (Transcription Factors) RN - 80295-54-1 (Complement C5a) RN - EC 1.14.14.1 (CYP1B1 protein, human) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1B1) RN - EC 2.7.11.22 (CDK6 protein, human) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 6) SB - IM MH - Acute Kidney Injury/etiology/*metabolism MH - Cells, Cultured MH - Cellular Senescence MH - Complement C5a/*physiology MH - Cyclin-Dependent Kinase 6/metabolism MH - Cytochrome P-450 CYP1B1/metabolism MH - *DNA Methylation MH - Epigenesis, Genetic MH - Epithelial Cells/metabolism MH - Humans MH - Kidney Tubules/*metabolism MH - Reperfusion Injury/etiology/*metabolism MH - Transcription Factors/metabolism MH - Wnt Signaling Pathway PMC - PMC6660044 OTO - NOTNLM OT - DNA methylation OT - acute kidney injury OT - complement cascade OT - renal Inflammaging COIS- CONFLICTS OF INTEREST: The authors of this manuscript have no conflicts of interest to disclose. EDAT- 2019/07/10 06:00 MHDA- 2020/07/22 06:00 PMCR- 2019/07/15 CRDT- 2019/07/09 06:00 PHST- 2019/03/08 00:00 [received] PHST- 2019/06/24 00:00 [accepted] PHST- 2019/07/10 06:00 [pubmed] PHST- 2020/07/22 06:00 [medline] PHST- 2019/07/09 06:00 [entrez] PHST- 2019/07/15 00:00 [pmc-release] AID - 102059 [pii] AID - 10.18632/aging.102059 [doi] PST - ppublish SO - Aging (Albany NY). 2019 Jul 8;11(13):4382-4406. doi: 10.18632/aging.102059.