Pentraxins are a family of evolutionarily conserved pattern recognition molecules with pivotal roles in innate immunity and inflammation, such as opsonization of pathogens during bacterial and... Show morePentraxins are a family of evolutionarily conserved pattern recognition molecules with pivotal roles in innate immunity and inflammation, such as opsonization of pathogens during bacterial and viral infections. In particular, the long Pentraxin 3 (PTX3) has been shown to regulate several aspects of vascular and tissue inflammation during solid organ transplantation.Our study investigated the role of PTX3 as possible modulator of Complement activation in a swine model of renal ischemia/reperfusion (I/R) injury.We demonstrated that I/R injury induced early PTX3 deposits at peritubular and glomerular capillary levels. Confocal laser scanning microscopy revealed PTX3 deposits co-localizing with CD31+ endothelial cells. In addition, PTX3 was associated with infiltrating macrophages (CD163), dendritic cells (SWC3a) and myofibroblasts (FSP1). In particular, we demonstrated a significant PTX3-mediated activation of classical (C1qmediated) and lectin (MBL-mediated) pathways of Complement. Interestingly, PTX3 deposits co-localized with activation of the terminal Complement complex (C5b-9) on endothelial cells, indicating that PTX3-mediated Complement activation occurred mainly at the renal vascular level. In conclusion, these data indicate that PTX3 might be a potential therapeutic target to prevent Complement-induced I/R injury. Show less
Bank, J.R.; Pol, P. van der; Vreeken, D.; Monge-Chaubo, C.; Bajema, I.M.; Schlagwein, N.; ... ; Kooten, C. van 2017
Conclusions/interpretation Taken together, circulating MBL levels are associated with diabetic nephropathy and are dependent on glycaemic control, possibly in an MBL2-genotype-dependent manner.
Shushimita, S.; Pol, P. van der; Bruin, R.W.F. de; Ijzermans, J.N.M.; Kooten, C. van; Dor, F.J.M.F. 2015
The aim of the research described in this thesis was to study the role of complement in renal ischemia/reperfusion injury (IRI) and to delineate the contribution of the different complement... Show moreThe aim of the research described in this thesis was to study the role of complement in renal ischemia/reperfusion injury (IRI) and to delineate the contribution of the different complement pathways involved. So far, in human renal IRI, the activation pathways of complement by ischemic proximal tubular epithelial cells (PTEC) are still incompletely elucidated. In chapter 2 we therefore established an in vitro model to simulate IRI on human and mouse PTEC by culturing these cells under normoxic or hypoxic conditions and then investigated the subsequent effects on complement activation following reoxygenation (reperfusion). We specifically focused on the question which pathway(s) of complement activation are initiated by human and mouse PTEC after hypoxic stress. In chapter 3 we addressed the lack of evidence for involvement of complement in human IRI. We assessed the formation and release of C5b-9 during early reperfusion in clinical kidney transplantation in living donor, brain-dead donor, and cardiac dead donor kidney transplantation. Complement activation following I/R may take place in both tubular and vascular compartments. Therefore, we systematically measured terminal complement activation during early reperfusion in human kidney transplantation in both the tubular compartment by immunohistochemistry and the intravascular compartment by selective arteriovenous measurements over the transplanted kidney. In chapter 4 we studied whether C5b-9 could also be detected in urines of transplant recipients early after transplantation. In addition, we investigated the possibility whether in proteinuric urine, which is common following transplantation, C5b-9 might be generated independent of a renal contribution. Based on previous clinical studies that high serum levels of MBL were associated with inferior renal allograft survival following clinical transplantation, we examined in chapter 5 the role of MBL in the pathophysiology of renal IRI and explored the therapeutic targeting of MBL in a rat model of renal IRI. We identified an entirely novel role for MBL in mediating reperfusion-induced kidney injury following ischemia which is completely independent of complement activation. In chapter 6 we studied the mechanism by which MBL might mediate tubular injury following renal I/R. Vascular leakage results in exposure of tubular cells to MBL, which was shown to be the primary culprit of tubular injury. Recombinant human C1 inhibitor (rhC1INH) is a serine protease inhibitor that inhibits complement activation, reduces vascular permeability and interacts with MBL. In chapter 7 we therefore explored the therapeutic application of rhC1INH in renal IRI and studied whether rhC1INH is able to attenuated MBL-mediated kidney injury. In chapter 8 we investigated the impact of short- and long-term IRI on vascular integrity, pericytes and angiopoietin expression. Finally, in chapter 9 the findings presented in this thesis are critically discussed and the possible implications for kidney transplantation are presented Show less
