زينة ضياء رزاق زوين

Properdin, a positive regulator of complement alternative pathway, participates in renal ischaemia-reperfusion (IR) injury, and also acts as a pattern-recognition molecule affecting apoptotic T cell clearance. However, the role of properdin in tubular epithelial cells (TECs) at the repair phase post IR injury is not well defined. This study revealed that properdin knockout (PKO) mice exhibited greater injury in renal function and histology than wild-type (WT) mice post 72-h IR, with more apoptotic cells and macrophages in tubular lumina, increased active caspase-3 and HMGB1, but better histological structure at 24 h. Raised erythropoietin receptor by IR was furthered by PKO and positively correlated with injury and repair markers. Properdin in WT kidneys was also up-regulated by IR, while H2O2-increased properdin in TECs was reduced by its siRNA, with raised HMGB1 and apoptosis. Moreover, the phagocytic ability of WT TECs, analyzed by pHrodo E. coli bioparticles, was promoted by H2O2, but inhibited by PKO. These results were confirmed by counting phagocytosed H2O2-induced apoptotic TECs by in situ end labelling fragmented DNAs, but not affected by additional serum with/without properdin. Taken together, PKO results in impaired phagocytosis at the repair phase post renal IR injury. Properdin locally produced by TECs plays crucial roles in optimizing damaged cells, regulating phagocytic ability of TECs and effectively clearing apoptotic cells and reducing inflammation.

Background and objectives: Kidneys from donation after circulatory death (DCD) are more likely to be declined for transplantation compared with kidneys from donation after brain death (DBD). The aim of this study was to evaluate characteristics in the biopsies of human DCD and DBD kidneys that were declined for transplantation in order to rescue more DCD kidneys. Materials and Methods: Sixty kidney donors (DCD= 36, DBD= 24) were recruited into the study and assessed using donor demographics. Kidney biopsies taken post cold storage were also evaluated for histological damage, inflammation (myeloperoxidase, MPO), von Willebrand factor (vWF) expression, complement 4d (C4d) deposition and complement 3 (C3) activation using H&E and immunohistochemistry staining, and Western blotting. Results: More DBD donors (16/24) had a history of hypertension compared with DCDs (8/36, p= 0.001). The mean warm ischemic time in the DCD kidneys was 12.9±3.9 min. The mean cold ischemic time was not significantly different between the two groups of kidney donors (DBD 33.3±16.7 vs. DCD 28.6±14.1 h, p> 0.05). The score of histological damage and MPO, as well as the reactivity of vWF, C4d and C3, varied between kidneys, but there was no significant difference between the two donor types (p> 0.05). However, vWF reactivity might be an early indicator for loss of tissue integrity, while C4d deposition and activated C3 might be better predictors for histological damage.

Renal ischemia-reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI), and may lead to chronic kidney disease. The high mortality rate of AKI has not changed in the last 5 decades due to non-recognition, nephrotoxin exposure, delayed diagnosis and lack of specific intervention. Complement activation plays important roles in IRI-induced AKI because of its association with immunity, inflammation, cell death and tissue repair. Nevertheless, the role of complement properdin, the sole positive regulator of the alternative pathway, in IRI-induced AKI has not been well defined. This review evaluates the dynamic changes and underlying mechanisms of complement activation with a focus on properdin in both in vitro and in vivo models challenged by hypoxia/reoxygenation and renal IRI. The multiple actions of properdin associated with HMGB1 and caspase-3, apoptosis and inflammation mediators, are discussed in the context of immunity, injury and repair at both the early and later stages of AKI. The complement activation-independent role of properdin and the effect of modulating properdin with or without genotype alteration are also addressed. Taking together, these might provide new mechanistic insights that potentially benefit timely diagnosis and specific intervention of IRI-induced AKI.

INTRODUCTION AND AIMS: Acute kidney injury (AKI) is a common problem associated with high mortality. Ischemia-reperfusion (IR) injury is one of the main causes of AKI. The heteroreceptor composed of EPO receptor (EPOR) and β-common receptor (βcR) is tissue protective. In addition, properdin is the only naturally occurring positive regulator of complement alternative pathway, stabilizing C3bBb and amplifying activation. Our previous study has demonstrated more severe renal damage in properdin deficient (PKO) mice than in wild type (WT) mice upon IR injury. The aim of this study was to explore the relationship between EPOR/βcR and properdin in kidney IR injury and repair. METHODS: The bilateral occlusion of renal pedicles for 30 min was performed in WT male C57BL/6 mice (n = 5-7), followed by reperfusion for 6 h, 12 h, 24 h, 48 h, 72 h, 1 w. In addition, PKO mice were studied at 72 h (n = 8), with matched WT mice (n = 9). A sham control group was also included for both sets of studies (n = 4-5). The expression of EPOR/βcR was measured, as along with renal function, tubulointerstitial damage (TID) score, apoptosis, high mobility group box 1 (HMGB1), active caspase-3 protein, mitosis and proliferating cell nuclear antigen (PCNA). RESULTS: In the time course model, the expression of EPOR/βcR gradually increased post IR injury from 6 h and reached a statistical significance at 72 h and 1 w compared to the sham control. The level of EPOR/βcR was not only positively associated with the injury marker of HMGB1 but also related to the repair related protein, PCNA. Moreover, properdin protein gradually increased from 6 h, peaked at 24 h and then declined, while its mRNA level remained low until 72 h and 1 w. Interestingly, properdin knockout mice demonstrated a further upregulation of EPOR/βcR in kidneys in contrast to the WT control at 72 h post IR. The upregulated EPOR/βcR was not only positively correlated with the level of renal functional and structural damage, apoptosis, HMGB1 and active caspase-3, but also significantly associated with mitotic figure and PCNA protein. CONCLUSIONS: Increased EPOR/βcR in kidneys relates to both IR injury and repair activities. Moreover, properdin deficiency further increased the level of EPOR/βcR at 72 h post IR injury. The biological significance and the mechanism of EPOR/βcR associated with properdin in renal IR injury and repair need to be further investigated

Introduction and Aims: Ischemia reperfusion injury (IRI) is a major cause of acute renal injury, affecting native and transplant kidneys alike. Properdin stabilizes C3bBb/(C3b)nBb and positively regulates the alternative pathway (AP) of complement activation, which may play key roles in the complex process of renal IRI. It has been previously described that renal IRI was accelerated in mice with deficiency of membrane bound negative regulators of complement activation, such as CD55 and CD59, and Crry. The aims of this study were to investigate the effect and mechanism of properdin deficiency (PKO) on renal IRI with focuses on apoptosis, inflammation and proliferation.

Abstract Proximal tubular epithelial cells are particularly sensitive to damage. In search of a biomarker, this study evaluated the potential of different cell activation models (hypoxia/replenishment and protein overload) to lead to a release of trefoil factor 3 (TFF3). Surprisingly, we found disparity in the ability of the different stimuli to enhance the intracellular abundance of TFF3 and its release: while conditions of nutrient starvation and damage associated with replenishment lead to intracellular abundance of TFF3 in the absence of TFF3 release, stimulation with an excess amount of albumin did not yield accumulation of TFF3. By contrast, incubation of cells with a purified λ light chain preparation from a patient with multiple myeloma provoked the presence of TFF3 in the cell supernatant. We, therefore, propose that elevations of TFF3 in renal disease might be more revelatory for the cause of restitution than previously thought.

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