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Hannover, Germany

Vallabhaneni K.C.,Hannover Medical School | Tkachuk S.,Hannover Medical School | Kiyan Y.,Hannover Medical School | Shushakova N.,Hannover Medical School | And 4 more authors.
Cardiovascular Research | Year: 2011

Aims Multipotent mesenchymal stem cells (MSCs) have regenerative properties and are recognized as putative players in the pathogenesis of cardiovascular diseases. The underlying molecular mechanisms remain, however, sparsely explored. Our study was designed to elucidate a probable role for the multifunctional urokinase (uPA)/urokinase receptor (uPAR) system in MSC regulation. Though uPAR has been implicated in a broad spectrum of pathophysiological processes, nothing is known about uPAR in MSCs. Methods and resultsuPAR was required to mobilize MSCs from the bone marrow (BM) of mice stimulated with granulocyte colony-stimulating factor (G-CSF) in vivo. An insignificant amount of MSCs was mobilized in uPAR-/- C57BL/6J mice, whereas in wild-type animals G-CSF induced an eight-fold increase of mobilized MSCs. uPAR-/- mice revealed up-regulated expression of G-CSF and stromal cell-derived factor 1 (CXCR4) receptors in BM. uPAR down-regulation leads to inhibition of human MSC migration, as shown in different migration assays. uPAR down- or up-regulation resulted in inhibition or stimulation of MSC differentiation into vascular smooth muscle cells (VSMCs) correspondingly, as monitored by changes in cell morphology and expression of specific marker proteins. Injection of fluorescently labelled MSCs in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice after femoral artery wire injury demonstrated impaired engraftment of uPAR-deficient MSCs at the place of injury. Conclusion sThese data suggest a multifaceted function of uPAR in MSC biology contributing to vascular repair. uPAR might guide and control the trafficking of MSCs to the vascular wall in response to injury or ischaemia and their differentiation towards functional VSMCs at the site of arterial injury. © 2010 The Author. Source


Wang L.,Hannover Medical School | Wang L.,Huazhong University of Science and Technology | Balzer M.S.,Hannover Medical School | Rong S.,Hannover Medical School | And 12 more authors.
Kidney International | Year: 2016

Chronic exposure to commercial glucose-based peritoneal dialysis fluids during peritoneal dialysis induces peritoneal membrane damage leading to ultrafiltration failure. In this study the role of protein kinase C (PKC) α in peritoneal membrane damage was investigated in a mouse model of peritoneal dialysis. We used 2 different approaches: blockade of biological activity of PKCα by intraperitoneal application of the conventional PKC inhibitor Go6976 in C57BL/6 wild-type mice and PKCα-deficient mice on a 129/Sv genetic background. Daily administration of peritoneal dialysis fluid for 5 weeks induced peritoneal upregulation and activation of PKCα accompanied by epithelial-to-mesenchymal transition of peritoneal mesothelial cells, peritoneal membrane fibrosis, neoangiogenesis, and macrophage and T cell infiltration, paralleled by reduced ultrafiltration capacity. All pathological changes were prevented by PKCα blockade or deficiency. Moreover, treatment with Go6976 and PKCα deficiency resulted in strong reduction of proinflammatory, profibrotic, and proangiogenic mediators. In cell culture experiments, both treatment with Go6976 and PKCα deficiency prevented peritoneal dialysis fluid–induced release of MCP-1 from mouse peritoneal mesothelial cells and ameliorated transforming growth factor-β1–induced epithelial-to-mesenchymal transition and peritoneal dialysis fluid–induced MCP-1 release in human peritoneal mesothelial cells. Thus, PKCα plays a crucial role in the pathophysiology of peritoneal membrane dysfunction induced by peritoneal dialysis fluids, and we suggest that its therapeutic inhibition might be a valuable treatment option for peritoneal dialysis patients. © 2016 International Society of Nephrology Source


Willenberg I.,University of Veterinary Medicine Hannover | Meschede A.K.,University of Veterinary Medicine Hannover | Gueler F.,Hannover Medical School | Jang M.-S.,Hannover Medical School | And 4 more authors.
PLoS ONE | Year: 2015

Epidemiologic studies show a correlation between the dietary intake of food polyphenols and beneficial health effects. Several in vitro studies indicate that the anti-inflammatory potential of polyphenols is, at least in part, mediated by a modulation of the enzymes of the arachidonic acid cascade, such as the prostaglandin forming cyclooxygenases (COXs). Evidence that this mode of action can be transferred to the situation in vivo is scarce. This study characterized effects of a subset of polyphenols on COX-2 expression and activity in vitro and compared the potency with known drugs. Next, the in vivo relevance of the observed in vitro effects was tested. Enzyme assays and incubations of polyphenols with the cancer cell line HCA-7 and lipopolysaccharide (LPS) stimulated primary monocytes support the hypothesis that polyphenols can effect COX-2 expression and activity in vitro. The effects were most pronounced in the monocyte assay for wogonin, apigenin, resveratrol and genistein with IC50 values of 1.5 μM, 2.6 μM, 2.8 μM and 7.4 μM. However, these values are 100- to 1000-fold higher in comparison to those of the known pharmaceuticals celecoxib, indomethacin and dexamethasone. In an animal model of LPS induced sepsis, pretreatment with polyphenols (i. p. 100 mg/kg bw) did not result in decreased plasma or tissue prostaglandin levels, whereas the positive control celecoxib effectively attenuated LPS induced prostaglandin formation. These data suggest that despite the moderate potency in vitro, an effect of polyphenols on COX-2 during acute inflammation is unlikely, even if a high dose of polyphenols is ingested. © 2015 Willenberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source


Hoehlig K.,Noxxon Pharma | Maasch C.,Noxxon Pharma | Shushakova N.,Phenos GmbH | Buchner K.,Noxxon Pharma | And 4 more authors.
Molecular Therapy | Year: 2013

Complement factor C5a is a potent proinflammatory mediator that contributes to the pathogenesis of numerous inflammatory diseases. Here, we describe the discovery of NOX-D20, a PEGylated biostable mirror-image mixed (l-)RNA/DNA aptamer (Spiegelmer) that binds to mouse and human C5a with picomolar affinity. In vitro, NOX-D20 inhibited C5a-induced chemotaxis of a CD88-expressing cell line and efficiently antagonized the activation of primary human polymorphonuclear leukocytes (PMN) by C5a. Binding of NOX-D20 to the C5a moiety of human C5 did not interfere with the formation of the terminal membrane attack complex (MAC). In sepsis, for which a specific interventional therapy is currently lacking, complement activation and elevated levels of C5a are suggested to contribute to multiorgan failure and mortality. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), NOX-D20 attenuated inflammation and organ damage, prevented the breakdown of the vascular endothelial barrier, and improved survival. Our study suggests NOX-D20 as a new therapeutic candidate for the treatment of sepsis. © The American Society of Gene & Cell Therapy. Source


Lu X.,Institute of Organ Transplantation | Li N.,The Center Hospital of Wuhan | Shushakova N.,Hannover Medical School | Shushakova N.,Phenos GmbH | And 10 more authors.
Journal of Nephrology | Year: 2012

Background: C57BL/6 and 129/Sv are the 2 most commonly used strains of mice in renal ischemia-reperfusion injury (IRI) studies, yet there are currently no studies that contrast differences in the degree of renal injury after ischemia-reperfusion. Methods: To evaluate renal IRI in male C57BL/6 and 129/Sv mice, we performed unilateral clamping of the left renal pedicle for 45 minutes and compared the degree of renal tissue damage and function. To measure function and tissue damage we examined: glomerular filtration rate (GFR; by inulin clearance), renal blood flow (RBF; by p-aminohippurate [PAH] clearance), renal morphology, immunohistochemistry for infiltrating leukocytes, and fibrogenic markers by Sirius red staining. Results: After unilateral IRI, 129/sv mice had significantly less GFR and RBF disfunction at both day 14 (d14) and d28. 129/sv mice also had significantly less acute tubular necrosis on d1 and fewer infiltrating leukocytes on d28, as well as less collagen deposition on d28 than C57BL/6 mice. Conclusions: C57BL/6 mice were much more sensitive to damage caused by renal IRI than are 129/Sv mice. © 2011 Società Italiana di Nefrologia. Source

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