Endothelial-to-mesenchymal transition and renal fibrosis in ischaemia/reperfusion injury are mediated by complement anaphylatoxins and Akt pathway.

Abstract

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.

• Authors: Claudia Curci, Giuseppe Castellano, Alessandra Stasi, Chiara Divella, Antonia Loverre, Margherita Gigante, Simona Simone, Marica Cariello, Vincenzo Montinaro, Giuseppe Lucarelli, Pasquale Ditonno, Michele Battaglia, Antonio Crovace, Francesco Staffieri, Beatrijs Oortwijn, Edwin van Amersfoort, Loreto Gesualdo, Giuseppe Grandaliano
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 29 Issue 4 Pg. 799-808 (Apr 2014) ISSN: 1460-2385 [Electronic] England
• PMID: 24463188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anaphylatoxins
• Proto-Oncogene Proteins c-akt

Topics

• Anaphylatoxins (metabolism)
• Animals
• Cells, Cultured
• Disease Models, Animal
• Endothelial Cells (metabolism, pathology)
• Female
• Fibroblasts (metabolism, pathology)
• Fibrosis (complications, metabolism, pathology)
• Humans
• Kidney (metabolism, pathology)
• Kidney Diseases (etiology, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reperfusion Injury (complications, metabolism, pathology)
• Signal Transduction
• Swine