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.
Castellano
Giuseppe
G
Department of Emergency and Organ Transplantation, University of Bari, Policlinico, Piazza Giulio Cesare 11, Bari, Italy. g.castellano@nephro.uniba.it
Melchiorre
Rita
R
Loverre
Antonia
A
Ditonno
Pasquale
P
Montinaro
Vincenzo
V
Rossini
Michele
M
Divella
Chiara
C
Battaglia
Michele
M
Lucarelli
Giuseppe
G
Annunziata
Gennaro
G
Palazzo
Silvano
S
Selvaggi
Francesco Paolo
FP
Staffieri
Francesco
F
Crovace
Antonio
A
Daha
Mohamed R
MR
Mannesse
Maurice
M
van Wetering
Sandra
S
Paolo Schena
Francesco
F
Grandaliano
Giuseppe
G
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