Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 20, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/ijms20153682
Keywords
LPS-binding protein; fibrosis; pericyte; myofibroblast; endotoxemia-induced oliguric kidney injury
Funding
- University of Bari Aldo Moro
- Italian Ministry of Health [GR-2011-02351027]
- Regional Strategic Grant, Apulia Region [PSR 094]
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During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFR beta expression and the dysfunctional alpha-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-beta, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFR beta and decreased alpha-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and alpha-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-beta signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-beta and underwent PMT also upon TGF-beta receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI.
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