Title |
Endothelial dysfunction and renal fibrosis in endotoxemia-induced oliguric kidney injury: possible role of LPS-binding protein
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Published in |
Critical Care, September 2014
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DOI | 10.1186/s13054-014-0520-2 |
Pubmed ID | |
Authors |
Giuseppe Castellano, Alessandra Stasi, Angelica Intini, Margherita Gigante, Anna Maria Di Palma, Chiara Divella, Giuseppe Stefano Netti, Clelia Prattichizzo, Paola Pontrelli, Antonio Crovace, Francesco Staffieri, Enrico Fiaccadori, Nicola Brienza, Giuseppe Grandaliano, Giovanni Pertosa, Loreto Gesualdo |
Abstract |
IntroductionThe pathophysiology of endotoxemia-induced acute kidney injury (AKI) is characterized by an intense activation of the host immune system and renal resident cells by lipopolysaccharide (LPS) and derived pro-inflammatory products. However, the occurrence of renal fibrosis in this setting has been poorly investigated. The aim of the present study was to investigate the possible association between endothelial dysfunction and acute development of tissue fibrosis in a swine model of LPS-induced AKI. Moreover we studied the possible effects of coupled plasma filtration adsorption (CPFA) in this setting.MethodsAfter 9 h from LPS infusion and 6 h of CPFA treatment, histological and biochemical changes were analyzed in pigs. Apoptosis and endothelial dysfunction were assessed on renal biopsies. The levels of LPS binding protein (LBP) were quantified by ELISA. Endothelial cells (EC) were stimulated in vitro with LPS and cultured in the presence of swine sera and were analyzed by FACS and Real time RT-PCR.ResultsIn a swine model of LPS-induced AKI, we observed that acute tubulointerstitial fibrosis occurred within 9 h from LPS injection. Acute fibrosis was associated with dysfunctional alpha-smooth muscle actin (¿-SMA)+ EC characterized by active proliferation (Ki-67+) without apoptosis (Caspase-3-). In accordance, LPS led to EC dysfunction in vitro with significant Vimentin and N-cadherin expressions and increased collagen I mRNA synthesis. Therapeutic intervention by citrate-based CPFA significantly prevented acute fibrosis in endotoxemic animals, by preserving EC phenotype both in peritubular capillaries and renal arteries. We found that the removal of LBP from plasma was crucial to eliminate the effects of LPS on EC dysfunction, by blocking LPS-induced collagen I production.ConclusionsOur data indicates that EC dysfunction might be pivotal in the acute development of tubulointerstitial fibrosis in LPS-induced AKI. Selective removal of the LPS adaptor protein LBP might represent a future therapeutic option to prevent EC dysfunction and tissue fibrosis in endotoxemia-induced AKI. |
X Demographics
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Unknown | 1 | 100% |
Demographic breakdown
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Practitioners (doctors, other healthcare professionals) | 1 | 100% |
Mendeley readers
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Brazil | 1 | 2% |
Unknown | 48 | 96% |
Demographic breakdown
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Researcher | 13 | 26% |
Other | 5 | 10% |
Student > Ph. D. Student | 5 | 10% |
Professor > Associate Professor | 4 | 8% |
Student > Master | 4 | 8% |
Other | 9 | 18% |
Unknown | 10 | 20% |
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Biochemistry, Genetics and Molecular Biology | 9 | 18% |
Agricultural and Biological Sciences | 3 | 6% |
Veterinary Science and Veterinary Medicine | 2 | 4% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 2% |
Other | 3 | 6% |
Unknown | 11 | 22% |