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Indianapolis, IN, United States

Breyer M.D.,Biotechnology Discovery Research
Seminars in Nephrology | Year: 2012

Diabetic nephropathy is the single major cause of kidney failure in the industrialized world and given the emerging global pandemic of diabetes mellitus, its prevalence is expected to only increase. Because of the lack of dynamic biomarkers that define the rate of kidney function loss, there are few proof-of-concept clinical trials for new therapeutics to treat diabetic nephropathy. A molecular understanding of the pathogenesis of diabetic nephropathy also is lacking. These deficiencies are magnified by the fact that most mouse models of diabetic nephropathy fail to show progressive kidney disease. Recently, some mouse models that showed requisite phenotypic changes of diabetic nephropathy have been identified. Validation of results obtained in these experimental models, and showing whether they accurately can predict clinical response to therapeutics in human diabetic nephropathy, must now be established.© 2012 Elsevier Inc.

Breyer M.D.,Biotechnology Discovery Research
Contributions to Nephrology | Year: 2011

The laboratory mouse is among the best characterized and flexible experimental platforms available for the study of diabetic nephropathy (DN). However, studies of progressive kidney disease in mice have underscored several important technical considerations for accurate phenotyping of renal function. Most mouse models of DN fail to exhibit progressive kidney disease. However, a few models have proved particularly useful. Despite the utility of these models, whether they can accurately predict clinical benefit of therapeutics in human DN remains to be established. Copyright © 2011 S. Karger AG, Basel.

Breyer M.D.,Biotechnology Discovery Research | Qi Z.,Biotechnology Discovery Research
Kidney International | Year: 2010

The use of creatinine to estimate glomerular filtration rate in patients is prone to well-described artifacts that impact its interpretation. Eisner et al. now show that the impact of creatinine secretion on creatinine clearance is even larger in mice than in humans, raising questions regarding the utility of creatinine for measuring glomerular filtration rate in mice. © 2010 International Society of Nephrology.

Theurl M.,Innsbruck Medical University | Nairz M.,Innsbruck Medical University | Schroll A.,Innsbruck Medical University | Sonnweber T.,Innsbruck Medical University | And 10 more authors.
Haematologica | Year: 2014

Anemia of chronic disease is a multifactorial disorder, resulting mainly from inflammation-driven reticuloendothelial iron retention, impaired erythropoiesis, and reduced biological activity of erythropoietin. Erythropoiesis-stimulating agents have been used for the treatment of anemia of chronic disease, although with varying response rates and potential adverse effects. Serum concentrations of hepcidin, a key regulator of iron homeostasis, are increased in patients with anemia of chronic disease and linked to the pathogenesis of this disease, because hepcidin blocks cellular iron egress, thus limiting availability of iron for erythropoiesis. We tested whether serum hepcidin levels can predict and affect the therapeutic efficacy of erythropoiesis-stimulating agent treatment using a well-established rat model of anemia of chronic disease. We found that high pre-treatment hepcidin levels correlated with an impaired hematologic response to an erythropoiesis-stimulating agent in rats with anemia of chronic disease. Combined treatment with an erythropoiesis-stimulating agent and an inhibitor of hepcidin expression, LDN-193189, significantly reduced serum hepcidin levels, mobilized iron from tissue stores, increased serum iron levels and improved hemoglobin levels more effectively than did the erythropoiesis-stimulating agent or LDN-193189 monotherapy. In parallel, both the erythropoiesis-stimulating agent and erythropoiesis-stimulating agent/LDN-193189 combined reduced the expression of cytokines known to inhibit erythropoiesis. We conclude that serum hepcidin levels can predict the hematologic responsiveness to erythropoiesis-stimulating agent therapy in anemia of chronic disease. Pharmacological inhibition of hepcidin formation improves the erythropoiesis-stimulating agent's therapeutic efficacy, which may favor a reduction of erythropoiesis-stimulating agent dosages, costs and side effects. © 2014 Ferrata Storti Foundation.

Schouten M.,University of Amsterdam | van der Sluijs K.F. .,University of Amsterdam | Gerlitz B.,Biotechnology Discovery Research | Grinnell B.W.,Biotechnology Discovery Research | And 4 more authors.
Critical Care | Year: 2010

Introduction: Influenza accounts for 5 to 10% of community-acquired pneumonias and is a major cause of mortality. Sterile and bacterial lung injuries are associated with procoagulant and inflammatory derangements in the lungs. Activated protein C (APC) is an anticoagulant with anti-inflammatory properties that exert beneficial effects in models of lung injury. We determined the impact of lethal influenza A (H1N1) infection on systemic and pulmonary coagulation and inflammation, and the effect of recombinant mouse (rm-) APC hereon.Methods: Male C57BL/6 mice were intranasally infected with a lethal dose of a mouse adapted influenza A (H1N1) strain. Treatment with rm-APC (125 μg intraperitoneally every eight hours for a maximum of three days) or vehicle was initiated 24 hours after infection. Mice were euthanized 48 or 96 hours after infection, or observed for up to nine days.Results: Lethal H1N1 influenza resulted in systemic and pulmonary activation of coagulation, as reflected by elevated plasma and lung levels of thrombin-antithrombin complexes and fibrin degradation products. These procoagulant changes were accompanied by inhibition of the fibrinolytic response due to enhanced release of plasminogen activator inhibitor type-1. Rm-APC strongly inhibited coagulation activation in both plasma and lungs, and partially reversed the inhibition of fibrinolysis. Rm-APC temporarily reduced pulmonary viral loads, but did not impact on lung inflammation or survival.Conclusions: Lethal influenza induces procoagulant and antifibrinolytic changes in the lung which can be partially prevented by rm-APC treatment. © 2010 Schouten et al.; licensee BioMed Central Ltd.

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