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Endothelial-to-mesenchymal transition and renal fibrosis in ischaemia/reperfusion injury are mediated by complement anaphylatoxins and Akt pathway
- Source :
- Università degli Studi di Milano-IRIS, Università degli studi di Foggia-IRIS
- Publication Year :
- 2014
- Publisher :
- Oxford University Press (OUP), 2014.
-
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.
- Subjects :
- Anaphylatoxins
Pathology
medicine.medical_specialty
Endothelium
Swine
Kidney
Peritubular capillaries
Fibrosis
medicine
Renal fibrosis
Settore MED/14 - NEFROLOGIA
Animals
Humans
complement
Anaphylatoxin
Cells, Cultured
PI3K/AKT/mTOR pathway
Transplantation
business.industry
Akt/PKB signaling pathway
Endothelial Cells
ischaemia/reperfusion
Fibroblasts
medicine.disease
endothelial-to-mesenchymal transition
Disease Models, Animal
medicine.anatomical_structure
Nephrology
Reperfusion Injury
Cancer research
Female
Kidney Diseases
business
Proto-Oncogene Proteins c-akt
Reperfusion injury
Signal Transduction
Subjects
Details
- ISSN :
- 14602385 and 09310509
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Nephrology Dialysis Transplantation
- Accession number :
- edsair.doi.dedup.....75cb6ce817478488506e784dd5e18bd2