Endothelial-to-mesenchymal transition and renal fibrosis in ischaemia/reperfusion injury are mediated by complement anaphylatoxins and Akt pathway.
BACKGROUND
Increasing evidence demonstrates a phenotypic plasticity of endothelial cells (ECs). Endothelial-to-mesenchymal transition (EndMT) contributes to the development of tissue fibrosis. However, the pathogenic factors and signalling pathways regulating this process in ischaemia/reperfusion (I/R) injury are still poorly understood.


METHODS
We investigated the possible role of complement in the induction of this endothelial dysfunction in a swine model of renal I/R injury by using recombinant C1 inhibitor in vivo.


RESULTS
Here, we showed that I/R injury reduced the density of renal peritubular capillaries and induced tissue fibrosis with generation of CD31(+)/α-SMA(+) and CD31(+)/FPS-1(+) cells indicating EndMT. When we inhibited complement, the process of EndMT became rare, with preserved density of peritubular capillaries and significant reduction in renal fibrosis. When we activated ECs by anaphylatoxins in vitro, C3a and C5a led to altered endothelial phenotype with increased expression of fibroblast markers and decrease expression of specific endothelial markers. The activation of Akt pathway was pivotal for the C3a and C5a-induced EndMT in vitro. In accordance, inhibition of complement in vivo led to the abrogation of Akt signalling, with hampered EndMT and tissue fibrosis.


CONCLUSIONS
Our data demonstrate a critical role for complement in the acute induction of EndMT via the Akt pathway. Therapeutic inhibition of these systems may be essential to prevent vascular damage and tissue fibrosis in transplanted kidney.
Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
Claudia
C
Curci
Giuseppe
G
Castellano
Alessandra
A
Stasi
Chiara
C
Divella
Antonia
A
Loverre
Margherita
M
Gigante
Simona
S
Simone
Marica
M
Cariello
Vincenzo
V
Montinaro
Giuseppe
G
Lucarelli
Pasquale
P
Ditonno
Michele
M
Battaglia
Antonio
A
Crovace
Francesco
F
Staffieri
Beatrijs
B
Oortwijn
Edwin
E
van Amersfoort
Loreto
L
Gesualdo
Giuseppe
G
Grandaliano
D000706:Anaphylatoxins / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013552:Swine
D000706:Anaphylatoxins; D051057:Proto-Oncogene Proteins c-akt
complement; endothelial-to-mesenchymal transition; ischaemia/reperfusion