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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; ENDOTHELIAL-CELLS ; Germany ; IN-VIVO ; THERAPY ; ACTIVATION ; LIGAND ; T-CELLS ; MOUSE ; transactivation ; SMOOTH-MUSCLE-CELLS ; hematology ; ACUTE KIDNEY INJURY ; PAR1 ; REDUCED ANTICOAGULANT ACTIVITY ; THROMBIN
    Abstract: The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPC-induced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies.
    Type of Publication: Journal article published
    PubMed ID: 22117049
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  • 2
    Keywords: CELL-PROLIFERATION ; MESSENGER-RNA ; FACTOR-KAPPA-B ; DIABETIC-NEPHROPATHY ; ACUTE KIDNEY INJURY ; STAGE EMBRYONIC-DEVELOPMENT ; LECTIN-LIKE DOMAIN ; COLD-SHOCK DOMAIN ; CHEMICAL ANOXIA ; TUBULAR CELLS
    Abstract: Ischemia-reperfusion injury (IRI) is the leading cause of ARF. A pathophysiologic role of the coagulation system in renal IRI has been established, but the functional relevance of thrombomodulin (TM)-dependent activated protein C (aPC) generation and the intracellular targets of aPC remain undefined. Here, we investigated the role of TM-dependent aPC generation and therapeutic aPC application in a murine renal IRI model and in an in vitro hypoxia and reoxygenation (HR) model using proximal tubular cells. In renal IRI, endogenous aPC levels were reduced. Genetic or therapeutic reconstitution of aPC efficiently ameliorated renal IRI independently of its anticoagulant properties. In tubular cells, cytoprotective aPC signaling was mediated through protease activated receptor-1- and endothelial protein C receptor-dependent regulation of the cold-shock protein Y-box binding protein-1 (YB-1). The mature 50 kD form of YB-1 was required for the nephro- and cytoprotective effects of aPC in vivo and in vitro, respectively. Reduction of mature YB-1 and K48-linked ubiquitination of YB-1 was prevented by aPC after renal IRI or tubular HR injury. aPC preserved the interaction of YB-1 with the deubiquitinating enzyme otubain-1 and maintained expression of otubain-1, which was required to reduce K48-linked YB-1 ubiquitination and to stabilize the 50 kD form of YB-1 after renal IRI and tubular HR injury. These data link the cyto- and nephroprotective effects of aPC with the ubiquitin-proteasome system and identify YB-1 as a novel intracellular target of aPC. These insights may provide new impetus for translational efforts aiming to restrict renal IRI.
    Type of Publication: Journal article published
    PubMed ID: 26015455
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  • 3
    Abstract: BACKGROUND: Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients. METHODS: Effects of ezetimibe on lipoprotein metabolism, hepatic and intestinal lipid content in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans were investigated. In order to investigate a possible effect of ezetimibe on cholesterol induced inflammation NF-kappaB activation as an indicator for inflammatory processes in liver and gut tissue was measured. RESULTS: Lipid enriched diet led to accumulation of lipids in hepatic tissue which caused strong hepatic NF-kappaB activation. Ezetimibe reduced lipid diet induced increase of circulating cholesterol by about 77% and prevent hepatic NF-kappaB activation almost completely. In contrast in intestinal cells Ezetimibe, though lowering diet induced cholesterol accumulation, increased triglyceride content and subsequent NF-kappaB activation. CONCLUSION: In summary these data show, that ezetimibe effectively reduced diet induced circulating cholesterol levels, hepatic lipid accumulation and inflammatory response in our guinea pig model. However this drug elicited a local inflammatory response in intestinal tissue. Whether these diverse effects of ezetimibe on inflammatory parameters such as NF-kappaB have clinical relevance remains to be determined.
    Type of Publication: Journal article published
    PubMed ID: 28167864
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  • 4
    Keywords: EXPRESSION ; MICE ; INFECTION ; EPITHELIAL-CELL LINE ; HEMOLYTIC-UREMIC SYNDROME ; COMPLEMENT ; OUTBREAK ; ENTEROHEMORRHAGIC ESCHERICHIA-COLI ; TOXIN-ASSOCIATED HUS ; ECULIZUMAB
    Abstract: The pathogenesis and therapy of Shigatoxin 2 (Stx2)-mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2-producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2-receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild-type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule-specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2-associated kidney failure (n = 11, aged 22-44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement-inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31-17.60) mg/dl, lactate dehydrogenase 1944 (753-2792) U/l, platelets 33 (19-124)/nl and haemoglobin 6.2 (5.2-7.8) g/dl; median (range)], all patients were discharged after 33 (range 19-43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84-2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66-1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate pathophysiological mechanism, importantly contributing to Stx2-mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only. (c) 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
    Type of Publication: Journal article published
    PubMed ID: 24909663
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  • 5
    Keywords: FAILURE, Germany, kidney, NEW-YORK, tumor, TUMORS, USA, XANTHOGRANULOMATOUS PYELONEPHRITIS
    Type of Publication: Journal article published
    PubMed ID: 18309351
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  • 6
    Keywords: ACTIVATION, ADJUVANT, ADJUVANT THERAPY, BACTEREMIA, CARE, CELLS, cholesterol, COENZYME-A REDUCTASE,
    Abstract: Statins, which are effective lipid-lowering drugs, also possess anti-inflammatory potential. However, circulating lipoproteins may also play a protective role during acute inflammatory diseases because of their ability to bind bacterial toxins. Low cholesterol levels have been reported in inflammatory conditions, and plasma cholesterol concentrations inversely correlate with severity and clinical outcome in septic patients. It is thus paradoxical that statins, which drastically reduce circulating cholesterol levels, should be beneficial in patients with inflammatory disease who are already hypocholesterolemic. We investigated the effect of simvastatin on LPS-induced nuclear factor kappa B (NF-kappa B) activation, TNF release, and mortality in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans. In the present study, simvastatin reduced circulating total and low-density lipoprotein cholesterol levels by 68% and 76%, respectively, and LPS-induced mortality from 73% to 20%. This reduction was accompanied by a significant reduction of NF-kappa B activation in the liver tissue, splenocytes, and plasma TNF levels by about 80%, 50%, and 77%, respectively. Our data suggest that simvastatin, despite lowering circulating low-density lipoprotein cholesterol, decreased LPS toxicity by reduction of NF-kappa B activation and subsequent release of TNF by modulating 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and therefore deserves consideration as a possible adjuvant therapy in acute inflammatory disease
    Type of Publication: Journal article published
    PubMed ID: 19008785
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  • 7
    Keywords: INHIBITION ; DISEASE ; validation ; ACTIVATION ; IMMUNITY ; immunosuppression ; RESVERATROL ; GLUCOCORTICOIDS ; Oxford classification ; MULTICENTER APPLICATION
    Abstract: IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways that can be impacted by corticosteroids. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for the treatment of IgAN, including resveratrol and hydroquinine. In summary, we have defined the distinct molecular profile of a pathologic phenotype associated with progressive renal insufficiency in IgAN. Exploration of the pathways associated with endocapillary proliferation confirms a molecular basis for the clinical effectiveness of corticosteroids in this subgroup of IgAN, and elucidates new therapeutic strategies for IgAN.
    Type of Publication: Journal article published
    PubMed ID: 25133636
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  • 8
    Keywords: IMPACT ; HLA ; FAILURE ; BIOPSIES ; II TYPE-1 RECEPTOR ; ANTIBODY-MEDIATED REJECTION ; DONOR-SPECIFIC ANTIBODIES ; MICROCIRCULATION INFLAMMATION ; CELL-TYPES ; C4D
    Abstract: BACKGROUND: Renal transplant glomerulitis (G) is associated with acute antibody-mediated rejection (ABMR) in the presence of donor-specific antibodies. However, the long-term prognosis of isolated G (isG) in the absence of donor-specific antibodies or G in combination with T cell-mediated rejection (TCMR) remains unexplored. METHODS: Seventy recipients with G were included in this retrospective study and subdivided into 3 groups: isG, G with TCMR (G + TCMR), and G with acute ABMR. The control groups were: patients with TCMR Banff type I or II without G (TCMR) and patients without rejection (NR). Kaplan-Meier death-censored survival plots and Cox regression were used to analyze graft survival. The combined graft survival endpoint was defined as a return to dialysis or estimated glomerular filtration rate less than 15 mL/min/1.73 m. The median follow-up was 37 (14; 77) months from biopsy. RESULTS: Graft survival was significantly lower in patients with G than in the NR and TCMR groups. No significant differences were observed among the isG, G + TCMR, and ABMR groups. Graft survival was lower in the G + TCMR group than in the TCMR group. Glomerulitis was independently associated with the risk of adverse graft outcome in a multivariate Cox regression model adjusted for other confounders (hazard ratio, 4.52 [95% confidence interval, 2.37-8.68] vs controls; P 〈 0.001). CONCLUSIONS: Glomerulitis is strongly associated with increased risk of graft failure. Graft survival in patients with isG that do not meet the Banff criteria for acute/active ABMR and in patients with G accompanying TCMR is comparable to the ABMR group.
    Type of Publication: Journal article published
    PubMed ID: 25594551
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  • 9
    Abstract: BACKGROUND & AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166) functions analogue to the receptor of advanced glycation end products, which has been implicated in the development of diabetic nephropathy (DN). We investigated the expression of ALCAM and its ligand S100B in patients with DN. METHODS: A total of 34 non-diabetic patients, 29 patients with type 2 diabetes and normal albuminuria and 107 patients with type 2 diabetes complicated with DN were assessed for serum concentration of soluble ALCAM (sALCAM) by ELISA. Expression of ALCAM and S100B in kidney histology from patients with DN was determined by immunohistochemistry. Cell expression of ALCAM and S100B was analyzed through confocal immunofluorescence microscopy. RESULTS: Serum concentration of sALCAM was increased in diabetic patients with DN compared to non-diabetic (59.85+/-14.99ng/ml vs. 126.88+/-66.45ng/ml, P〈0.0001). Moreover sALCAM correlated positively with HbA1c (R=0.31, P〈0.0001), as well as with the stages of chronic kidney disease and negatively correlated with eGFR (R=-0.20, P〈0.05). In diabetic patients with normal albuminuria sALCAM was increased compared to patients with DN (126.88+/-66.45ng/ml vs. 197.50+/-37.17ng/ml, P〈0.0001). In diabetic patients, ALCAM expression was significantly upregulated in both the glomeruli and tubules (P〈0.001). ALCAM expression in the glomeruli correlated with presence of sclerosis (R=0.25, P〈0.001) and localized mainly in the podocytes supporting the hypothesis that membrane bound ALCAM drives diabetic nephropathy and thus explaining sALCAM decrease in diabetic patients with DN. The expression of S100B was increased significantly in the glomeruli of diabetic patients (P〈0.001), but not in the tubules. S100B was as well localized in the podocytes. CONCLUSIONS: This study identifies for the first time ALCAM as a potential mediator in the late complications of diabetes in the kidney.
    Type of Publication: Journal article published
    PubMed ID: 28325697
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  • 10
    Abstract: Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918 biopsies with DN revealed strong evidence that these mechanisms are connected to each other, wherein excess GBM components fail to undergo degradation and are deposited in the mesangium. These data do not exclude that mesangial cells also synthesize components that contribute to the accumulation of matrix in the mesangium. Light, electron microscopic, immunofluorescence, and in situ hybridization studies clearly show that the thickening of the GBM is due not only to overproduction of components of the mature GBM (alpha3 and alpha5 chains of collagen IV and agrin) by podocytes but also to resumed increased synthesis of the alpha1 chain of collagen IV and of perlecan by endothelial cells usually seen during embryonic development. We hypothesize that these abnormal production mechanisms are caused by different processes: overproduction of mature GBM-components by the diabetic milieu and regression of endothelial cells to an embryonic production mode by decreased availability of mediators from podocytes.
    Type of Publication: Journal article published
    PubMed ID: 28228399
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