Therapeutic targeting of classical and lectin pathways of complement protects from ischemia-reperfusion-induced renal damage.
Ischemia-reperfusion injury is the major cause of delayed graft function in transplanted kidneys, an early event significantly affecting long-term graft function and survival. Several studies in rodents suggest that the alternative pathway of the complement system plays a pivotal role in renal ischemia-reperfusion injury. However, limited information is currently available from humans and larger animals. Here we demonstrated that 30 minutes of ischemia resulted in the induction of C4d/C1q, C4d/MLB, and MBL/MASP-2 deposits in a swine model of ischemia-reperfusion injury. The infusion of C1-inhibitor led to a significant reduction in peritubular capillary and glomerular C4d and C5b-9 deposition. Moreover, complement-inhibiting treatment significantly reduced the numbers of infiltrating CD163(+), SWC3a(+), CD4a(+), and CD8a(+) cells. C1-inhibitor administration led to significant inhibition of tubular damage and tubular epithelial cells apoptosis. Interestingly, we report that focal C4d-deposition colocalizes with C1q and MBL at the peritubular and glomerular capillary levels also in patients with delayed graft function. In conclusion, we demonstrated the activation and a pathogenic role of classical and lectin pathways of complement in a swine model of ischemia-reperfusion-induced renal damage. Therefore, inhibition of these two pathways might represent a novel therapeutic approach in the prevention of delayed graft function in kidney transplant recipients.
Department of Emergency and Organ Transplantation, University of Bari, Policlinico, Piazza Giulio Cesare 11, Bari, Italy. g.castellano@nephro.uniba.it
Giuseppe
G
Castellano
Rita
R
Melchiorre
Antonia
A
Loverre
Pasquale
P
Ditonno
Vincenzo
V
Montinaro
Michele
M
Rossini
Chiara
C
Divella
Michele
M
Battaglia
Giuseppe
G
Lucarelli
Gennaro
G
Annunziata
Silvano
S
Palazzo
Francesco Paolo
FP
Selvaggi
Francesco
F
Staffieri
Antonio
A
Crovace
Mohamed R
MR
Daha
Maurice
M
Mannesse
Sandra
S
van Wetering
Francesco
F
Paolo Schena
Giuseppe
G
Grandaliano
D000818:Animals; D050718:Complement C1 Inhibitor Protein / Q000096:biosynthesis; D015922:Complement C1q / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007511:Ischemia / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D037102:Lectins / Q000737:chemistry*; D010446:Peptide Fragments / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D013552:Swine
D050718:Complement C1 Inhibitor Protein; D037102:Lectins; D010446:Peptide Fragments; D015922:Complement C1q; D015935:Complement C4b; C032261:complement C4d; D003165:Complement System Proteins