Complement Modulation of Anti-Aging Factor Klotho in Ischemia/Reperfusion Injury and Delayed Graft Function.
Klotho is an anti-aging factor mainly produced by renal tubular epithelial cells (TEC) with pleiotropic functions. Klotho is down-regulated in acute kidney injury in native kidney; however, the modulation of Klotho in kidney transplantation has not been investigated. In a swine model of ischemia/reperfusion injury (IRI), we observed a remarkable reduction of renal Klotho by 24 h from IRI. Complement inhibition by C1-inhibitor preserved Klotho expression in vivo by abrogating nuclear factor kappa B (NF-kB) signaling. In accordance, complement anaphylotoxin C5a led to a significant down-regulation of Klotho in TEC in vitro that was NF-kB mediated. Analysis of Klotho in kidneys from cadaveric donors demonstrated a significant expression of Klotho in pre-implantation biopsies; however, patients affected by delayed graft function (DGF) showed a profound down-regulation of Klotho compared with patients with early graft function. Quantification of serum Klotho after 2 years from transplantation demonstrated significant lower levels in DGF patients. Our data demonstrated that complement might be pivotal in the down-regulation of Klotho in IRI leading to a permanent deficiency after years from transplantation. Considering the anti-senescence and anti-fibrotic effects of Klotho at renal levels, we hypothesize that this acquired deficiency of Klotho might contribute to DGF-associated chronic allograft dysfunction.
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
G
G
Castellano
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
A
A
Intini
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
A
A
Stasi
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
C
C
Divella
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
M
M
Gigante
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
P
P
Pontrelli
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
R
R
Franzin
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
M
M
Accetturo
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
A
A
Zito
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
M
M
Fiorentino
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
V
V
Montinaro
Urology, Andrology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
G
G
Lucarelli
Urology, Andrology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
P
P
Ditonno
Urology, Andrology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
M
M
Battaglia
Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
A
A
Crovace
Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
F
F
Staffieri
Pharming Group NV, Leiden, the Netherlands.
B
B
Oortwijn
Pharming Group NV, Leiden, the Netherlands.
E
E
van Amersfoort
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
G
G
Pertosa
Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
G
G
Grandaliano
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
L
L
Gesualdo
D058186:Acute Kidney Injury / Q000601:surgery; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D015936:Complement C5a / Q000494:pharmacology*; D051799:Delayed Graft Function / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006085:Graft Survival; D006801:Humans; D007124:Immunoenzyme Techniques; D007155:Immunologic Factors / Q000494:pharmacology; D016030:Kidney Transplantation / Q000009:adverse effects*; D000090265:Klotho Proteins; D011183:Postoperative Complications; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D014184:Transplantation, Homologous
D007155:Immunologic Factors; D012333:RNA, Messenger; D015936:Complement C5a; D005966:Glucuronidase; D000090265:Klotho Proteins
basic (laboratory) research/science; complement biology; immunobiology; ischemia reperfusion injury (IRI); kidney transplantation/nephrology