Abstract
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 PDGFRβ expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-β, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRβ and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-β signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-β and underwent PMT also upon TGF-β 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.
Highlights
Sepsis is a multi-organ disease and represents a systemic immune response to a bacterial infection
In healthy and coupled plasma filtration adsorption (CPFA)-treated healthy pigs (T9 CTR, T9 CPFA, Figure 1A), PDGFRβ+ expression was detected in interstitial peritubular capillaries, in mesangial cells, and Bowman’s capsule. 9 h after LPS infusion, we found a significant reduction of PDGFRβ expression in endotoxemic pigs at peritubular capillary level (T9 LPS) (Figure 1C); on the contrary, PDGFRβ expression of mesangial cells was not significantly down-regulated, as expected [21]
To investigate whether the PDGFRβ decrease could be associated with occurrence of pericyte-to-myofibroblast trans-differentiation (PMT), we performed a double immunofluorescence for both PDGFRβ and α-SMA marker
Summary
Sepsis is a multi-organ disease and represents a systemic immune response to a bacterial infection. Sepsis is the major cause of acute kidney injury (AKI) and is associated with high mortality or risk of chronic kidney disease (CKD) [1]. The pathophysiology of sepsis-induced AKI is complex and characterized by an overwhelming inflammatory response that leads to metabolic dysfunction, tubular damage, and microvascular dysfunction [2,3]. The most common bacteria involved in sepsis-induced AKI are gram-negative, since their outer wall component, named lipopolysaccharide (LPS) or endotoxin, can activate a wide variety of cells through interaction with specific pattern recognition receptors (PRR), such as TLRs (toll-like receptors) [4]. The cellular response to endotoxin requires a shuttle protein—LPS-binding protein (LBP)—that brings LPS to TLR4 and maximizes intracellular signaling [7,8,9,10,11,12]
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