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Dive into the research topics where Mario Schiffer is active.

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Featured researches published by Mario Schiffer.


Journal of Immunology | 2008

Activated Renal Macrophages Are Markers of Disease Onset and Disease Remission in Lupus Nephritis

Lena Schiffer; Ramalingam Bethunaickan; Meera Ramanujam; Weiqing Huang; Mario Schiffer; Haiou Tao; Michael M. Madaio; Erwin P. Bottinger; Anne Davidson

Costimulatory blockade with CTLA4Ig and anti-CD40L along with a single dose of cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice. To understand the mechanisms for remission and for impending relapse, we examined the expression profiles of 61 inflammatory molecules in the perfused kidneys of treated mice and untreated mice at different stages of disease. Further studies using flow cytometry and immunohistochemistry allowed us to determine the cellular origins of several key markers. We show that only a limited set of inflammatory mediators is expressed in the kidney following glomerular immune complex deposition but before the onset of proteinuria. Formation of a lymphoid aggregate in the renal pelvis precedes the invasion of the kidney by inflammatory cells. Regulatory molecules are expressed early in the disease process and during remission but do not prevent the inevitable progression of active inflammation. Onset of proliferative glomerulonephritis and proteinuria is associated with activation of the renal endothelium, expression of chemokines that mediate glomerular cell infiltration, and infiltration by activated dendritic cells and macrophages that migrate to different topographical areas of the kidney but express a similar profile of inflammatory cytokines. Increasing interstitial infiltration by macrophages and progressive tubular damage, manifested by production of lipocalin-2, occur later in the disease process. Studies of treated mice identify a type II (M2b)-activated macrophage as a marker of remission induction and impending relapse and suggest that therapy for systemic lupus erythematosus nephritis should include strategies that prevent both activation of monocytes and their migration to the kidney.


Journal of Immunology | 2003

Short Term Administration of Costimulatory Blockade and Cyclophosphamide Induces Remission of Systemic Lupus Erythematosus Nephritis in NZB/W F1 Mice by a Mechanism Downstream of Renal Immune Complex Deposition

Lena Schiffer; Jayashree Sinha; Xiaobo Wang; Weiqing Huang; Gero von Gonsdorff; Mario Schiffer; Michael P. Madaio; Anne Davidson

NZB/W F1 mice with established nephritis were treated with a single dose of cyclophosphamide with or without a 2-wk course of murine CTLA4Ig, either alone or in combination with anti-CD154. Sixty to 80% of treated mice entered remission, and remission could be reinduced following relapse. A decrease in the frequency of anti-DNA-producing B cells and activated T cells was observed in treated mice, but this effect lasted only 3–6 wk, while remissions were sustained for up to 20 wk. Light microscopy of the kidneys of mice in remission revealed less glomerular inflammation, less tubular damage, and less infiltration of inflammatory cells. By immunofluorescence, however, IgG and C3 staining of glomeruli was no different in treated mice vs controls. Since chemokines and their receptors play an important role in inflammatory cell infiltration of affected organs in autoimmune diseases, we examined chemokine expression in the kidneys. Decreases in the expression of inflammatory cytokines and chemokines were evident in mice in the early stages of remission, but these differences were no longer present in late remission. Increased expression of CXCL13 was detected in the inflammatory infiltrates of the control NZB/NZW mice. Strikingly, we could not detect any CXCL13 in the kidneys of the treated group even in late remission. These findings suggest that costimulatory blockade together with cyclophosphamide influence the activation state of renal CD11c-positive cells and therefore lead to less B and T cell infiltration and nephritis.


The Lancet | 2011

Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial

Andreas Greinacher; Sigrun Friesecke; Peter Abel; Alexander Dressel; Sylvia Stracke; Michael Fiene; Friedlinde Ernst; Kathleen Selleng; Karin Weissenborn; Bernhard M.W. Schmidt; Mario Schiffer; Stephan B. Felix; Markus M. Lerch; Jan T. Kielstein; Julia Mayerle

BACKGROUND In May 2011, an outbreak of Shiga toxin-producing enterohaemorrhagic E coli O104:H4 in northern Germany led to a high proportion of patients developing post-enteritis haemolytic uraemic syndrome and thrombotic microangiopathy that were unresponsive to therapeutic plasma exchange or complement-blocking antibody (eculizumab). Some patients needed ventilatory support due to severe neurological complications, which arose 1 week after onset of enteritis, suggesting an antibody-mediated mechanism. Therefore, we aimed to assess immunoadsorption as rescue therapy. METHODS In our prospective non-controlled trial, we enrolled patients with severe neurological symptoms and confirmed recent E coli O104:H4 infection without other acute bacterial infection or raised procalcitonin concentrations. We did IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days, followed by IgG replacement (0·5 g/kg intravenous IgG). We calculated a composite neurological symptom score (lowest score was best) every day and assessed changes before and after immunoadsorption. FINDINGS We enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8·0 days (range 5-12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8·0 days (range 5-15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3·0 (SD 1·1, p=0·038), and improved to 1·0 (1·2, p=0·0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery. INTERPRETATION Antibodies are probably involved in the pathogenesis of severe neurological symptoms in patients with E coli O104:H4-induced haemolytic uraemic syndrome. Immunoadsorption can safely be used to rapidly ameliorate these severe neurological complications. FUNDING Greifswald University and Hannover Medical School.


Journal of The American Society of Nephrology | 2005

Novel Regulators of Kidney Development from the Tips of the Ureteric Bud

Kai M. Schmidt-Ott; Jun Yang; Xia Chen; Howard Wang; Neal Paragas; Kiyoshi Mori; Jau-Yi Li; Benson Lu; Frank Costantini; Mario Schiffer; Erwin P. Bottinger; Jonathan Barasch

Mammalian nephrogenesis depends on the interaction between the ureteric bud and the metanephric mesenchyme. As the ureteric bud undergoes branching and segmentation, the stalks differentiate into the collecting system of the mature kidney, while the tip cells interact with the adjacent cells of the metanephric mesenchyme, inducing their conversion into nephrons. This induction is mediated by secreted factors. For identifying novel mediators, the tips of the ureteric tree were isolated and microarray analyses were performed using manually refined, multistep gene ontology annotations. For identifying conserved factors, two databases were developed, one from mouse E12.5 and one from rat E13.5 ureteric buds. The overlap of mouse and rat data sets yielded 20 different transcripts that were enriched in the ureteric bud compared with metanephric mesenchyme and predicted to code for secreted proteins. Real-time reverse transcriptase-PCR and in situ hybridization confirmed these identifications. One of the genes that was highly specific to the ureteric bud tip was cytokine-like factor 1 (CLF-1). Recombinant CLF-1 in complex with its physiologic ligand, cardiotrophin-like cytokine (CLC), triggered phosphorylation of signal transducer and activator of transcription 3 in mesenchyme, a pathway characteristic of mesenchymal-to-epithelial conversion. Indeed, when applied to isolated rat metanephric mesenchyme, CLF-1/CLC (3 nM) induced mature nephron structures expressing glomerular and tubular markers. These results underline the power of this first comprehensive gene expression analysis of the ureteric bud tip to identify bioactive molecules.


Journal of Clinical Investigation | 2011

CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival

Suma Yaddanapudi; Mehmet M. Altintas; Andreas D. Kistler; Isabel Fernandez; Clemens C. Möller; Changli Wei; Vasil Peev; Jan Flesche; Anna Lena Forst; Jing Li; Jaakko Patrakka; Zhijie Xiao; Florian Grahammer; Mario Schiffer; Tobias Lohmüller; Thomas Reinheckel; Changkyu Gu; Tobias B. Huber; Wenjun Ju; Markus Bitzer; Maria Pia Rastaldi; Phillip Ruiz; Karl Tryggvason; Andrey S. Shaw; Christian Faul; Sanja Sever; Jochen Reiser

Kidney podocytes are highly differentiated epithelial cells that form interdigitating foot processes with bridging slit diaphragms (SDs) that regulate renal ultrafiltration. Podocyte injury results in proteinuric kidney disease, and genetic deletion of SD-associated CD2-associated protein (CD2AP) leads to progressive renal failure in mice and humans. Here, we have shown that CD2AP regulates the TGF-β1-dependent translocation of dendrin from the SD to the nucleus. Nuclear dendrin acted as a transcription factor to promote expression of cytosolic cathepsin L (CatL). CatL proteolyzed the regulatory GTPase dynamin and the actin-associated adapter synaptopodin, leading to a reorganization of the podocyte microfilament system and consequent proteinuria. CD2AP itself was proteolyzed by CatL, promoting sustained expression of the protease during podocyte injury, and in turn increasing the apoptotic susceptibility of podocytes to TGF-β1. Our study identifies CD2AP as the gatekeeper of the podocyte TGF-β response through its regulation of CatL expression and defines a molecular mechanism underlying proteinuric kidney disease.


Nephrology Dialysis Transplantation | 2011

Increase of infectious complications in ABO-incompatible kidney transplant recipients—a single centre experience

Antje Habicht; Verena Bröker; Cornelia Blume; Johan M. Lorenzen; Mario Schiffer; Nikolaus Richter; J. Klempnauer; Hermann Haller; Frank Lehner; Anke Schwarz

BACKGROUND Due to the shortage of deceased donors ABO-incompatible (ABOi) living kidney transplantation has become a popular alternative to deceased kidney transplantation. In recent years, recipient desensitization with a combination of anti-CD20 treatment (rituximab), antigen-specific immunoadsorptions (IA) and intravenous immunoglobulin (IVIG), led to promising short-term and intermediate-term results. However, little is known about the impact of this intensified desensitization protocol on the risk of surgical and infectious complications. METHODS We retrospectively analysed 21 consecutive recipients who underwent ABOi renal transplantation. Pre-transplant desensitization included administration of rituximab (375 mg/m(2)), mycophenolate mofetil (MMF), tacrolimus and prednisolone 4 weeks prior of scheduled transplantation as well as IA and IVIG. Forty-seven patients who underwent ABO-compatible (ABOc) renal transplantation served as the control group. Medical records and electronic databases were reviewed for patient and graft survival, renal function, rate of rejections, viral and bacterial infections as well as for surgical complications (SCs) post-transplantation. RESULTS All patients showed an immediate graft function. During a mean follow-up of 15.7 ± 8.3 months (interquartile range 11.9) patient survival was 95 and 98% in the ABOi and ABOc group, respectively. Allograft survival and function, as assessed by serum creatinine levels and calculated glomerular filtration rate at 1 year, did not differ between ABOi and ABOc recipients. Furthermore, the rate of biopsy-proven acute rejections was comparable between the two groups. However, there was a trend towards more SCs within the ABOi group (29 versus 11%, non-significant). In addition, the rate of viral infections including cytomegalovirus, Herpes simplex virus, Varicella zoster virus and polyoma virus was significantly increased among the ABOi recipients (50 versus 21%; P = 0.038) despite comparable tacrolimus trough levels and MMF and steroid doses. CONCLUSIONS Our results, in line with the extended experience of other groups, demonstrate favourable short-term allograft survival and function after ABOi renal transplantation after desensitization with antigen-specific IA, IVIG and rituximab. However, the intensified desensitization was associated with an increased risk of infectious complications. This observation prompted us to briefly escalate the desensitization protocol in ABOi kidney recipients in our centre.


Nephrology Dialysis Transplantation | 2011

The podocyte as a direct target of immunosuppressive agents

Eva Schönenberger; Jochen H. H. Ehrich; Hermann Haller; Mario Schiffer

Podocytes play a key role in maintaining the blood-urine barrier for high-molecular-weight proteins. They are considered to be terminally differentiated, and podocyte loss cannot be compensated by regenerative proliferation. Various diseases leading to podocyte damage and loss result in proteinuria and cause nephrotic syndrome. Therefore, direct therapeutical strategies to protect podocytes in disease situations are a logical concept to prevent disease or to delay disease progression. Acquired podocytopathies like idiopathic focal segmental glomerulosclerosis and minimal change disease are historically considered as immunological diseases. Therefore, immunosuppressive agents such as steroids and calcineurin inhibitors are the commonly used treatment strategies. However, the causative disease mechanisms behind these treatment strategies remain elusive. Recent evidence shows that immunosuppressive agents, in addition to the effect on the immune system, directly influence the unique structure and function of podocytes. In this context, the actin cytoskeleton of the podocyte and cytokines such as vascular endothelial growth factor play a pivotal role. In this review, we summarize the direct effects on podocytes obtained in vivo and in vitro after treatment with calcineurin inhibitors, mTOR inhibitors and glucocorticoids. These direct effects could play a key role in the treatment concepts of podocytopathies with an important impact on the long-term renal function in patients with pharmacological immunosuppression.


Journal of The American Society of Nephrology | 2009

Loss of Podocyte aPKCλ/ι Causes Polarity Defects and Nephrotic Syndrome

Tobias B. Huber; Björn Hartleben; Kirstin Winkelmann; Lisa Schneider; Jan U. Becker; Michael Leitges; Gerd Walz; Hermann Haller; Mario Schiffer

Atypical protein kinase C (aPKC) is a central component of the evolutionarily conserved Par3-Par6-aPKC complex, one of the fundamental regulators of cell polarity. We recently demonstrated that these proteins interact with Neph-nephrin molecules at the slit diaphragm of the glomerular filtration barrier. Here, we report that podocyte-specific deletion of aPKClambda/iota in mice results in severe proteinuria, nephrotic syndrome, and death at 4 to 5 wk after birth. Podocyte foot processes of knockout mice developed structural defects, including mislocalization of the slit diaphragm. In the glomerulus, aPKClambda/iota was primarily expressed in developing glomerular epithelial cells and podocyte foot processes. Interestingly, under physiologic conditions, aPKClambda/iota translocated from the apical surface to the basolateral side of developing podocytes, and this translocation preceded the development of foot processes and formation of slit diaphragms. Supporting a critical role for aPKClambda/iota in the maintenance of slit diaphragms and podocyte foot processes, aPKClambda/iota associated with the Neph-nephrin slit diaphragm complex and localized to the tips of filopodia and leading edges of cultured podocytes. These results suggest that aPKC signaling is fundamental to glomerular maintenance and development.


Journal of The American Society of Nephrology | 2002

Inhibitory Smads and TGF-β Signaling in Glomerular Cells

Mario Schiffer; Lena Schiffer; Arti Gupta; Andrey S. Shaw; Ian S. Roberts; Peter Mundel; Erwin P. Bottinger

ABSTRACT. Smad6 and Smad7 are inhibitory SMADs with putative functional roles at the intersection of major intracellular signaling networks, including TGF-β, receptor tyrosine kinase (RTK), JAK/STAT, and NF-κB pathways. This study reports differential functional roles and regulation of Smad6 and Smad7 in TGF-β signaling in renal cells, in murine models of renal disease and in human glomerular diseases. Smad7 is upregulated in podocytes in all examined glomerular diseases (focal segmental glomerulosclerosis [FSGS], minimal-change disease [MCD], membranous nephropathy [MNP], lupus nephritis [LN], and diabetic nephropathy [DN]) with a statistically significant upregulation in “classical” podocyte-diseases such as FSGS and MCD. TGF-β induces Smad7 synthesis in cultured podocytes and Smad6 synthesis in cultured mesangial cells. Although Smad7 expression inhibited both Smad2- and Smad3-mediated TGF-β signaling in podocytes, it inhibited only Smad3 but not Smad2 signaling in mesangial cells. In contrast, Smad6 had no effect on TGF-β/Smad signaling in podocytes and enhanced Smad3 signaling in mesangial cells. These data suggest that Smad7 is activated in injured podocytes in vitro and in human glomerular disease and participates in negative control of TGF-β/Smad signaling in addition to its pro-apoptotic activity, whereas Smad6 has no role in TGF-β response and injury in podocytes. In contrast, Smad6 is upregulated in the mesangium in human glomerular diseases and may be involved in functions independent of TGF-β/Smad signaling. These data indicate an important role for Smad6 and Smad7 in glomerular cells in vivo that could be important for the cell homeostasis in physiologic and pathologic conditions.


Journal of The American Society of Nephrology | 2014

Mutations in the Gene That Encodes the F-Actin Binding Protein Anillin Cause FSGS

Rasheed Gbadegesin; Gentzon Hall; Adebowale Adeyemo; Nils Hanke; Irini Tossidou; James L. Burchette; Alison Homstad; Matthew A. Sparks; Jose A. Gomez; Andrea S. Alonso; Peter Lavin; Peter J. Conlon; Ron Korstanje; M. Christine Stander; Ghaidan Shamsan; Moumita Barua; Robert F. Spurney; Pravin C. Singhal; Jeffrey B. Kopp; Hermann Haller; David N. Howell; Martin R. Pollak; Andrey S. Shaw; Mario Schiffer; Michelle P. Winn

FSGS is characterized by segmental scarring of the glomerulus and is a leading cause of kidney failure. Identification of genes causing FSGS has improved our understanding of disease mechanisms and points to defects in the glomerular epithelial cell, the podocyte, as a major factor in disease pathogenesis. Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS. We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS. We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1-associated nephropathy. Overexpression of R431C mutant ANLN in immortalized human podocytes results in enhanced podocyte motility. The mutant anillin displays reduced binding to the slit diaphragm-associated scaffold protein CD2AP. Knockdown of the ANLN gene in zebrafish morphants caused a loss of glomerular filtration barrier integrity, podocyte foot process effacement, and an edematous phenotype. Collectively, these findings suggest that anillin is important in maintaining the integrity of the podocyte actin cytoskeleton.

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Beina Teng

Hannover Medical School

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Patricia Schroder

Mount Desert Island Biological Laboratory

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Jan Menne

Hannover Medical School

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Lynne Staggs

Mount Desert Island Biological Laboratory

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Heiko Schenk

Hannover Medical School

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