Hermann-Josef Gröne

Publications (129)960.13 Total impact

• Article: Inhibition of Comt with tolcapone slows progression of polycystic kidney disease in the more severely affected PKD/Mhm (cy/+) substrain of the Hannover Sprague-Dawley rat.

  Susanne N E Boehn, Sonja Spahn, Sabine Neudecker, Andrea Keppler, Marie-Thérèse Bihoreau, Bettina Kränzlin, Priyanka Pandey, Sigrid C Hoffmann, Li Li, Vicente E Torres, Hermann-Josef Gröne, Norbert Gretz
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  ABSTRACT: Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human inherited diseases. Modifier genes seem to modulate the disease progression and might therefore be promising drug targets. Although a number of modifier loci have been already identified, no modifier gene has been proven to be a real modifier yet.Methods Gene expression profiling of two substrains of the Han:SPRD rat, namely PKD/Mhm and PKD/US, both harboring the same mutation, was conducted in 36-day-old animals. Catechol-O-methyltransferase (Comt) was identified as a potential modifier gene. A 3-month treatment with tolcapone, a selective inhibitor of Comt, was carried out in PKD/Mhm and PKD/US (cy/+) animals.ResultsComt is localized within a known modifier locus of PKD (MOP2). The enzyme encoding gene was found upregulated in the more severely affected PKD/Mhm substrain and was hence presumed to be a putative modifier gene of PKD. The treatment with tolcapone markedly attenuated the loss of renal function, inhibited renal enlargement, shifted the size distribution of renal cysts and retarded cell proliferation, apoptosis, inflammation and fibrosis development in affected (cy/+) male and female PKD/Mhm and PKD/US rats.Conclusions Comt has been confirmed to be the first reported modifier gene for PKD and tolcapone offers a promising drug for treating PKD.
  Nephrology Dialysis Transplantation 03/2013; · 3.40 Impact Factor
• Article: Iron Regulatory Proteins Control a Mucosal Block to Intestinal Iron Absorption.

  Bruno Galy, Dunja Ferring-Appel, Christiane Becker, Norbert Gretz, Hermann-Josef Gröne, Klaus Schümann, Matthias W Hentze
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  ABSTRACT: Mammalian iron metabolism is regulated systemically by the hormone hepcidin and cellularly by iron regulatory proteins (IRPs) that orchestrate a posttranscriptional regulatory network. Through ligand-inducible genetic ablation of both IRPs in the gut epithelium of adult mice, we demonstrate that IRP deficiency impairs iron absorption and promotes mucosal iron retention via a ferritin-mediated "mucosal block." We show that IRP deficiency does not interfere with intestinal sensing of body iron loading and erythropoietic iron need, but rather alters the basal expression of the iron-absorption machinery. IRPs thus secure sufficient iron transport across absorptive enterocytes by restricting the ferritin "mucosal block" and define a basal set point for iron absorption upon which IRP-independent systemic regulatory inputs are overlaid.
  Cell reports. 03/2013;
• Article: Cell-specific in vivo functions of glycosphingolipids: lessons from genetic deletions of enzymes involved in glycosphingolipid synthesis.

  Richard Jennemann, Hermann-Josef Gröne
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  ABSTRACT: Glycosphingolipids (GSLs) are believed to be involved in many cellular events including trafficking, signaling and cellular interactions. Over the past decade considerable progress was made elucidating the function of GSLs by generating and exploring animal models with GSL-deficiency. Initial studies focused on exploring the role of complex sialic acid containing GSLs (gangliosides) in neuronal tissue. Although complex gangliosides were absent, surprisingly, the phenotype observed was rather mild. In subsequent studies, several mouse models with combinations of gene-deletions encoding GSL-synthesizing enzymes were developed. The results indicated that reduction of GSL-complexity correlated with severity of phenotypes. However, in these mice, accumulation of precursor GSLs or neobiosynthesized GSL-series seemed to partly compensate the loss of GSLs. Thus, UDP-glucose:ceramide glucosyltransferase (Ugcg), catalyzing the basic step of the glucosylceramide-based GSL-biosynthesis, was genetically disrupted. A total systemic deletion of Ugcg caused early embryonic lethality. Therefore, Ugcg was eliminated in a cell-specific manner using the cre/loxP-system. New insights into the cellular function of GSLs were gained. It was demonstrated that neurons require GSLs for differentiation and maintenance. In keratinocytes, preservation of the skin barrier depend on GSL synthesis and in enterocytes of the small intestine GSLs are involved in endocytosis and vesicular transport.
  Progress in lipid research 03/2013; · 10.67 Impact Factor
• Article: Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

  Viola Nordström, Monja Willershäuser, Silke Herzer, Jan Rozman, Oliver von Bohlen Und Halbach, Sascha Meldner, Ulrike Rothermel, Sylvia Kaden, Fabian C Roth, Clemens Waldeck, Norbert Gretz, Martin Hrabě de Angelis, Andreas Draguhn, Martin Klingenspor, Hermann-Josef Gröne, Richard Jennemann
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  ABSTRACT: Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.
  PLoS Biology 03/2013; 11(3):e1001506. · 11.45 Impact Factor
• Article: Endogenous and exogenous pentraxin-3 limits postischemic acute and chronic kidney injury.

  Maciej Lech, Christoph Römmele, Regina Gröbmayr, Heni Eka Susanti, Onkar P Kulkarni, Shijun Wang, Hermann-Josef Gröne, Bernd Uhl, Christoph Reichel, Fritz Krombach, Cecilia Garlanda, Alberto Mantovani, Hans-Joachim Anders
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  ABSTRACT: Ischemia-reperfusion activates innate immunity and sterile inflammation, resulting in acute kidney injury. Since pentraxin 3 (PTX3) regulates multiple aspects of innate immunity and tissue inflammation, we tested whether PTX3 would be involved in renal ischemia-reperfusion injury. Renal pedicle clamping increased PTX3 serum levels, as well as PTX3 expression, inside the kidney but predominantly in CD45/CD11c(+) cells, a subpopulation of intrarenal mononuclear phagocytes. Lack of PTX3 aggravated postischemic acute kidney injury as evidenced by massive tubular necrosis, and TNF and IL-6 release, as well as massively increased neutrophil and macrophage infiltrates at 24 h. This was followed by tubular atrophy, interstitial fibrosis, and kidney shrinking 10 weeks later. In vivo microscopy uncovered increased leukocyte adhesion and transmigration in postischemic microvessels of Ptx3-deficient mice. Furthermore, injection of recombinant PTX3 up to 6 h after reperfusion prevented renal leukocyte recruitment and postischemic kidney injury. Thus, local PTX3 release from a subpopulation of intrarenal mononuclear phagocytes or delayed PTX3 treatment limits postischemic renal inflammation. Conversely, Ptx3 loss-of-function mutations predispose to postischemic acute kidney injury and subsequent chronic kidney disease.Kidney International advance online publication, 16 January 2013; doi:10.1038/ki.2012.463.
  Kidney International 01/2013; · 6.61 Impact Factor
• Article: Lipid Droplet Accumulation Is Associated with an Increase in Hyperglycemia-Induced Renal Damage: Prevention by Liver X Receptors.

  Eva Kiss, Bettina Kränzlin, Katja Wagenblaβ, Mahnaz Bonrouhi, Joachim Thiery, Elisabeth Gröne, Viola Nordström, Daniel Teupser, Norbert Gretz, Ernst Malle, Hermann-Josef Gröne
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  ABSTRACT: Dyslipidemia is a frequent component of the metabolic disorder of diabetic patients contributing to organ damage. Herein, in low-density lipoprotein receptor-deficient hyperlipidemic and streptozotozin-induced diabetic mice, hyperglycemia and hyperlipidemia acted reciprocally, accentuating renal injury and altering renal function. In hyperglycemic-hyperlipidemic kidneys, the accumulation of Tip47-positive lipid droplets in glomeruli, tubular epithelia, and macrophages was accompanied by the concomitant presence of the oxidative stress markers xanthine oxidoreductase and nitrotyrosine, findings that could also be evidenced in renal biopsy samples of diabetic patients. As liver X receptors (LXRα,β) regulate genes linked to lipid and carbohydrate homeostasis and inhibit inflammatory gene expression in macrophages, the effects of systemic and macrophage-specific LXR activation were analyzed on renal damage in hyperlipidemic-hyperglycemic mice. LXR stimulation by GW3965 up-regulated genes involved in cholesterol efflux and down-regulated proinflammatory/profibrotic cytokines, inhibiting the pathomorphology of diabetic nephropathy, renal lipid accumulation, and improving renal function. Xanthine oxidoreductase and nitrotyrosine levels were reduced. In macrophages, GW3965 or LXRα overexpression significantly suppressed glycated or acetylated low-density lipoprotein-induced cytokines and reactive oxygen species. Specifically, in mice, transgenic expression of LXRα in macrophages significantly ameliorated hyperlipidemic-hyperglycemic nephropathy. The results demonstrate the presence of lipid droplet-induced oxidative mechanisms and the pathophysiologic role of macrophages in diabetic kidneys and indicate the potent regulatory role of LXRs in preventing renal damage in diabetes.
  American Journal Of Pathology 01/2013; · 4.89 Impact Factor
• Article: Growth arrest-specific protein 1 is a novel endogenous inhibitor of glomerular cell activation and proliferation.

  Claudia R C van Roeyen, Stephanie Zok, Jessica Pruessmeyer, Peter Boor, Yoshikuni Nagayama, Stefan Fleckenstein, Clemens D Cohen, Frank Eitner, Hermann-Josef Gröne, Tammo Ostendorf, Andreas Ludwig, Jürgen Floege
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  ABSTRACT: Growth arrest-specific protein-1 (GAS1) is a GPI-anchored protein which is highly expressed in embryonic mouse fibroblasts and inhibits their proliferation. Glomerular mesangial cells release soluble GAS1 protein into the supernatant in vitro. Growth arrest led to GAS1 overexpression and increased release. Secretion involved disintegrin and metalloproteinase 10 and 17 as signified by inhibition experiments. Recombinant soluble GAS1 protein inhibited the proliferation of mesangial cells. Conversely, the induction of mesangial cell proliferation by PDGF-BB or -DD led to downregulation of GAS1 mRNA. Specific ligands of the PDGF α-receptor, PDGF-AA and -CC, had no effect. The GAS1 protein was localized in podocytes in kidneys from healthy rats. During the time course of mesangioproliferative glomerulonephritis in anti-Thy1.1-treated rats, glomerular GAS1 expression decreased prior to the onset of mesangial cell proliferation and increased at later stages during glomerular recovery. Finally, a plasmid expressing soluble GAS1 fused to an Fc fragment was systemically overexpressed in rats with mesangioproliferative glomerulonephritis. This ameliorated renal damage was indicated by decreased albuminuria and serum creatinine. Gas1/Fc-transfected rats also exhibited a reduction of the glomerular mesangial cell activation and proliferation. Thus, GAS1 is a novel endogenous inhibitor of glomerular mesangial cell proliferation and may be a novel therapeutic target in mesangioproliferative glomerular diseases.Kidney International advance online publication, 19 December 2012; doi:10.1038/ki.2012.400.
  Kidney International 12/2012; · 6.61 Impact Factor
• Article: Globosides but not isoglobosides can impact the development of invariant NKT cells and their interaction with dendritic cells.

  Stefan Porubsky, Anneliese O Speak, Mariolina Salio, Richard Jennemann, Mahnaz Bonrouhi, Rashad Zafarulla, Yogesh Singh, Julian Dyson, Bruno Luckow, Agnes Lehuen, Ernst Malle, Johannes Müthing, Frances M Platt, Vincenzo Cerundolo, Hermann-Josef Gröne
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  ABSTRACT: Recognition of endogenous lipid Ag(s) on CD1d is required for the development of invariant NKT (iNKT) cells. Isoglobotrihexosylceramide (iGb3) has been implicated as this endogenous selecting ligand and recently suggested to control overstimulation and deletion of iNKT cells in α-galactosidase A-deficient (αGalA(-/-)) mice (human Fabry disease), which accumulate isoglobosides and globosides. However, the presence and function of iGb3 in murine thymus remained controversial. In this study, we generate a globotrihexosylceramide (Gb3)-synthase-deficient (Gb3S(-/-)) mouse and show that in thymi of αGalA(-/-)/Gb3S(-/-) double-knockout mice, which store isoglobosides but no globosides, minute amounts of iGb3 can be detected by HPLC. Furthermore, we demonstrate that iGb3 deficiency does not only fail to impact selection of iNKT cells, in terms of frequency and absolute numbers, but also does not alter the distribution of the TCR CDR 3 of iNKT cells. Analyzing multiple gene-targeted mouse strains, we demonstrate that globoside, rather than iGb3, storage is the major cause for reduced iNKT cell frequencies and defective Ag presentation in αGalA(-/-) mice. Finally, we show that correction of globoside storage in αGalA(-/-) mice by crossing them with Gb3S(-/-) normalizes iNKT cell frequencies and dendritic cell (DC) function. We conclude that, although detectable in murine thymus in αGalA(-/-)/Gb3S(-/-) mice, iGb3 does not influence either the development of iNKT cells or their interaction with peripheral DCs. Moreover, in αGalA(-/-) mice, it is the Gb3 storage that is responsible for the decreased iNKT cell numbers and impeded Ag presentation on DCs.
  The Journal of Immunology 08/2012; 189(6):3007-17. · 5.79 Impact Factor
• Article: Glycosphingolipids are essential for intestinal endocytic function.

  Richard Jennemann, Sylvia Kaden, Roger Sandhoff, Viola Nordström, Shijun Wang, Martina Volz, Sylvie Robine, Nicole Amen, Ulrike Rothermel, Herbert Wiegandt, Hermann-Josef Gröne
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  ABSTRACT: Glycosphingolipids (GSLs) constitute major components of enterocytes and were hypothesized to be potentially important for intestinal epithelial polarization. The enzyme UDP-glucose ceramide glucosyltransferase (Ugcg) catalyzes the initial step of GSL biosynthesis. Newborn and adult mice with enterocyte-specific genetic deletion of the gene Ugcg were generated. In newborn mutants lacking GSLs at day P0, intestinal epithelia were indistinguishable from those in control littermates displaying an intact polarization with regular brush border. However, those mice were not consistently able to absorb nutritional lipids from milk. Between postnatal days 5 and 7, severe defects in intestinal epithelial differentiation occurred accompanied by impaired intestinal uptake of nutrients. Villi of mutant mice became stunted, and enterocytes lacked brush border. The defects observed in mutant mice caused diarrhea, malabsorption, and early death. In this study, we show that GSLs are essential for enterocyte resorptive function but are primarily not for polarization; GSLs are required for intracellular vesicular transport in resorption-active intestine.
  Journal of Biological Chemistry 07/2012; 287(39):32598-616. · 4.77 Impact Factor
• Article: Behandlung der idiopathischen membranösen Glomerulonephritis

  Martin Busch, Jens Gerth, Undine Ott, Andre Schip, Christoph C. Haufe, Hermann-Josef Gröne, Gunter Wolf
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  ABSTRACT: Hintergrund:Die membranöse Glomerulonephritis (MGN) ist durch eine Proteinurie > 3,5 g/d und weitere Symptome des nephrotischen Syndroms gekennzeichnet. In vielen Fällen ist die Ätiologie idiopathisch. Ob und wie die MGN zu behandeln ist, bleibt kontrovers. Trotz der Therapie mit Kortikosteroiden, Ciclosporin oder Alkylanzien entwickeln bis zu 40% der Patienten eine terminale Niereninsuffizienz. Fallbeschreibung:Ein 40-jähriger Patient mit nierenbioptisch gesicherter idiopathischer MGN wurde aufgrund der hohen initialen Proteinurie von 22 g/d bei einer normalen Nierenfunktion mit Chlorambucil und Prednisolon behandelt. Da das nephrotische Syndrom nach 6 Monaten persistierte, wurde eine Ciclosporintherapie begonnen. Die Proteinurie konnte durch diese Therapie bis auf 4 g/d gesenkt werden. Diese Therapie wurde nach 17 Monaten beendet, und es kam zum schnellen Wiederauftreten des nephrotischen Syndroms. Eine erneute Nierenbiopsie zeigte eine MGN im Stadium II, teils III nach Ehrenreich & Churg ohne wesentlichen chronischen tubulointerstitiellen Schaden. Eine Therapie mit ACE-Hemmern und AT1-Rezeptor-Antagonisten sowie die erneute Ciclosporingabe reduzierten nochmals die Proteinurie. Ciclosporin wurde nach insgesamt 24 Monaten abgesetzt. 5 Monate danach kam es zu einem erneuten Rezidiv der Erkrankung mit einer Proteinurie bis 34 g/d. Der monoklonale Anti-CD20-Antikörper Rituximab wurde in einer Dosis von 4 × 375 mg/m2 alle 4 Wochen zusätzlich zu einer Prednisolontherapie verabreicht. Nach 4 Wochen reduzierte sich die Proteinurie auf 780 mg/d, 4 Monate nach Therapieende betrug sie < 150 mg/d. Die Nierenfunktion blieb allerdings reduziert (Kreatininclearance 65 ml/min, Stadium 2 nach K/DOQI). 2 Jahre nach Beendigung der Rituximabgabe ist die Proteinurie in anhaltend stabiler Remission (< 150 mg/d). Die Nierenfunktion verschlechterte sich jedoch weiter (Kreatininclearance 45 ml/min, Stadium 3 nach K/DOQI). Schlussfolgerung:Rituximab eröffnet die Möglichkeit einer zielgerichteten Therapie der idiopathischen MGN. Auf der Basis der existierenden Evidenz kann Rituximab als eine neue Therapieoption der MGN, wahrscheinlich noch vor dem Einsatz zytotoxischer Substanzen und hochdosierter Prednisolongaben, die das Risiko schwerer Nebenwirkungen haben, empfohlen werden. Langzeitergebnisse dieser Therapie sind allerdings noch nicht verfügbar. Background:Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure. Case Report:A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT1 receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m2) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and < 150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (< 150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI). Conclusion:Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.
  04/2012; 103(7):519-524.
• Article: Wechsel zwischen BK-Virus-Nephropathie und Abstoßung – der frustrane Verlauf einer Lebendnierenspende

  Christine Materne, Jens Gerth, Undine Ott, Hermann-Josef Gröne, Gunter Wolf
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  ABSTRACT: Fallbeschreibung: Ein 56-jähriger dialysepflichtiger Patient erhielt im Juni 2007 eine Lebendnierenspende von seiner Ehefrau. Die initiale Immunsuppression bestand aus Prednisolon, Tacrolimus und Mycophenolatmofetil (MMF). 4 Monate nach Transplantation trat ein Kreatininanstieg auf 192 μmol/l (normal: 74–110 μmol/l) auf. Der Urinbefund zeigte einen hohen Anteil von Decoyzellen. In der Transplantatnierenbiopsie zeigte sich das Bild einer fokal akzentuierten mittelschweren interstitiellen Nephritis. Immunhistologisch wiesen zahlreiche Kerne von Tubuli eine Expression des SV40-Antigens auf. In der Polymerase-Kettenreaktion (PCR) des Urins (5,8 × 1011 Kopien/ml) und des Serums (1,9 × 104 Kopien/ml) war BK-Virus nachweisbar. Es wurde zunächst Tacrolimus abgesetzt und mit 20 mg Leflunomid/Tag begonnen (Zielspiegel 40–100 ng/ml). MMF wurde auf 2 × 500 mg halbiert. 1 Monat später erfolgte die erneute stationäre Einweisung bei weiterer Verschlechterung der Nierenfunktion (Kreatininanstieg auf 262 μmol/l). Der Leflunomidspiegel lag im Zielbereich. In der Urinzytologie waren weiter Decoyzellen nachweisbar. In der Transplantatbiopsie fanden sich keine Zeichen der Rejektion, jedoch weiterhin eine persistierende floride Polyomavirusinfektion. Die MMF-Therapie wurde beendet. Die Therapie mit Leflunomid und Prednisolon (5 mg) wurde belassen. Im Verlauf war eine Stabilisierung der Transplantatfunktion (Kreatinin 233 μmol/l) zu erzielen. Die PCR auf BK-Virus im Serum war jetzt negativ. Bei einem erneuten Kreatininanstieg auf 308 μmol/l im April 2008 war in der erneuten Transplantatbiopsie SV40-Antigen nicht mehr nachzuweisen, es zeigte sich jedoch eine floride interstitielle Rejektion. Die Immunsuppression wurde durch Ciclosporin A ergänzt und eine Methylprednisolonstoßtherapie über 5 Tage durchgeführt. Nach initialer Stabilisierung der Transplantatfunktion war innerhalb weniger Wochen ein deutlicher Kreatininanstieg auf 444 μmol/l zu verzeichnen. In der Nierenbiopsie zeigte sich eine interstitielle Rejektion mit jetzt erneut zusätzlichem geringen Nachweis von SV40-Antigen. Die Nierenfunktion verschlechterte sich weiter. Bei fortgeschrittenem Schaden wurde auf eine Intensivierung der Immunsuppression verzichtet und, der Patient musste wieder in die Dialyse eingegliedert werden. Schlussfolgerung: Die BK-Virus-Nephropathie ist eine seltene, aber im Zunehmen begriffene Komplikation nach Nierentransplantation, vermutlich aufgrund intensiverer Immunsuppression. Die Erkrankung kann zu einer nachhaltigen Funktionsverschlechterung der transplantierten Niere bis zum Transplantatversagen führen. Eine BK-Virus-Infektion kann eine Abstoßung triggern. Leider ist die Therapie bezüglich der Immunsuppression bei BK-Virus- Nephropathie und Abstoßung völlig gegensätzlich: Bei einer BK-Virus- Nephropathie ist eine Reduktion, bei der akuten Abstoßung eine Intensivierung der Immunsuppression notwendig. Ein möglicher Ausweg kann die Behandlung mit Leflunomid sein, einer immunsuppressiven Substanz mit antiviraler Wirkung, die allerdings im Einzelfall erhebliche Nebenwirkungen haben kann. Der beschriebene Fall zeigt den frustranen Verlauf einer Nierenlebendspende trotz initial erfolgreicher Therapie mit Leflunomid und verdeutlicht die Probleme einer Balance zwischen intensiver und moderater Immunsuppression. Case Report: A 56-year-old male patient with terminal renal insufficiency received a living donor kidney transplant from his wife in June 2007. Initial immunosuppression consisted of prednisolone, tacrolimus, and mycophenolate mofetil (MMF). 4 months after transplantation, the serum creatinine increased to 192 μmol/l and urinary analysis revealed the presence of decoy cells. A biopsy showed a focal interstitial nephritis and SV40 antigen was detected in tubular nuclei. Polymerase chain reaction (PCR) in serum and urine showed high titers of BK virus. Tacrolimus was stopped, MMF was reduced, and leflunomide (20 mg/day) was started. The patient was readmitted because the serum creatinine further increased to 262 μmol/l. Leflunomide concentrations were in the target range, but renal biopsy still revealed the presence of BK virus nephropathy. MMF was stopped. Serum creatinine stabilized at 233 μmol/l and PCR for BK virus in serum was negative. In April 2008, a deterioration of renal function occurred (serum creatinine 308 μmol/l) and renal biopsy revealed signs of acute interstitial rejection without the presence of SV40 antigen. A methylprednisolone pulse therapy for 5 days was performed and cyclosporine was added. After a few weeks serum creatinine increased to 444 μmol/l and a new biopsy revealed the reoccurrence of BK virus nephropathy. Since the tubulointerstitial injury was > 80%, no further therapy was performed and soon after dialysis therapy was initiated. Conclusion: BK virus nephropathy is a still rare, but increasing complication of renal transplantation, presumably mediated by intensive immunosuppression. The disease can induce graft dysfunction and may ultimately lead to graft failure. BK virus nephropathy can trigger acute rejection. Unfortunately, therapy of BK virus nephropathy and acute rejection is just the opposite: BK virus nephropathy requires a reduction of immunosuppression whereas acute rejection calls for intensification. A potential therapeutic approach may be leflunomide, an immunosuppressive substance with antiviral properties, but potential severe side effects. The described case demonstrates the frustrating course of a graft from a living donor despite initial successful therapy with leflunomide and illustrates the problems choosing between intensive and moderate immunosuppression.
  04/2012; 104(8):644-648.
• Article: Loss of ceramide synthase 3 causes lethal skin barrier disruption.

  Richard Jennemann, Mariona Rabionet, Karin Gorgas, Sharon Epstein, Alexander Dalpke, Ulrike Rothermel, Aline Bayerle, Franciscus van der Hoeven, Silke Imgrund, Joachim Kirsch, Walter Nickel, Klaus Willecke, Howard Riezman, Hermann-Josef Gröne, Roger Sandhoff
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  ABSTRACT: The stratum corneum as the outermost epidermal layer protects against exsiccation and infection. Both the underlying cornified envelope (CE) and the intercellular lipid matrix contribute essentially to these two main protective barriers. Epidermis-unique ceramides with ultra-long-chain acyl moities (ULC-Cers) are key components of extracellular lipid lamellae (ELL) and are bound to CE proteins, thereby contributing to the cornified lipid envelope (CLE). Here, we identified human and mouse ceramide synthase 3 (CerS3), among CerS1-6, to be exclusively required for the ULC-Cer synthesis in vitro and of mouse CerS3 in vivo. Deficiency of CerS3 in mice results in complete loss of ULC-Cers (≥C26), lack of continuous ELL and a non-functional CLE. Consequently, newborn mutant mice die shortly after birth from transepidermal water loss. Mutant skin is prone to Candida albicans infection highlighting ULC-Cers to be pivotal for both barrier functions. Persistent periderm, hyperkeratosis and deficient cornification are hallmarks of mutant skin demonstrating loss of Cers to trigger a keratinocyte maturation arrest at an embryonic pre-barrier stage.
  Human Molecular Genetics 02/2012; 21(3):586-608. · 7.64 Impact Factor
• Article: Lineage specification of parietal epithelial cells requires β-catenin/Wnt signaling.

  Stephan Grouls, Diana Margarita Iglesias, Nicolas Wentzensen, Marcus Johannes Moeller, Maxime Bouchard, Rolf Kemler, Paul Goodyer, Felix Niggli, Hermann-Josef Gröne, Wilhelm Kriz, Robert Koesters
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  ABSTRACT: β-Catenin/Wnt signaling is essential during early inductive stages of kidney development, but its role during postinductive stages of nephron development and maturation is not well understood. In this study, we used Pax8Cre mice to target β-catenin deficiency to renal epithelial cells at the late S-shaped body stage and the developing collecting ducts. The conditional β-catenin knockout mice formed abnormal kidneys and had reduced renal function. The kidneys were hypoplastic with a thin cortex; a superficial layer of tubules was missing. A high proportion of glomeruli had small, underdeveloped capillary tufts. In these glomeruli, well differentiated podocytes replaced parietal epithelial cells in Bowman's capsule; capillaries toward the outer aspect of these podocytes mimicked the formation of glomerular capillaries. Tracing nephrogenesis in embryonic conditional β-catenin knockout mice revealed that these "parietal podocytes" derived from precursor cells in the parietal layer of the S-shaped body by direct lineage switch. Taken together, these findings demonstrate that β-catenin/Wnt signaling is important during the late stages of nephrogenesis and for the lineage specification of parietal epithelial cells.
  Journal of the American Society of Nephrology 01/2012; 23(1):63-72. · 9.66 Impact Factor
• Article: Successful prenatal mannose treatment for congenital disorder of glycosylation-Ia in mice.

  Anette Schneider, Christian Thiel, Jan Rindermann, Charles DeRossi, Diana Popovici, Georg F Hoffmann, Hermann-Josef Gröne, Christian Körner
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  ABSTRACT: Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic Pmm2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.
  Nature medicine 12/2011; 18(1):71-3. · 27.14 Impact Factor
• Article: The proteoglycan biglycan enhances antigen-specific T cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis.

  Zoran V Popovic, Shijun Wang, Maria Papatriantafyllou, Ziya Kaya, Stefan Porubsky, Maria Meisner, Mahnaz Bonrouhi, Sven Burgdorf, Marian F Young, Liliana Schaefer, Hermann-Josef Gröne
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  ABSTRACT: Biglycan is a proteoglycan ubiquitously present in extracellular matrix of a variety of organs, including heart, and it was reported to be overexpressed in myocardial infarction. Myocardial infarction may be complicated by perimyocarditis through unknown mechanisms. Our aim was to investigate the capacity of TLR2/TLR4 ligand biglycan to enhance the presentation of specific Ags released upon cardiomyocyte necrosis. In vitro, OVA-pulsed bone marrow-derived dendritic cells from wild-type (WT; C57BL/6) and TLR2-, TLR4-, MyD88-, or TRIF-deficient mice were cotreated with LPS, biglycan, or vehicle and incubated with OVA-recognizing MHC I- or MHC II-restricted T cells. Biglycan enhanced OVA-specific cross-priming by >80% to MHC I-restricted T cells in both TLR2- and TLR4-pathway-dependent manners. Accordingly, biglycan-induced cross-priming by both MyD88- and TRIF-deficient dendritic cells (DCs) was strongly diminished. OVA-specific activation of MHC II-restricted T cells was predominantly TLR4 dependent. Our first in vivo correlate was a model of experimental autoimmune perimyocarditis triggered by injection of cardiac Ag-pulsed DCs (BALB/c). Biglycan-treated DCs triggered perimyocarditis to a comparable extent and intensity as LPS-treated DCs (mean scores 1.3 ± 0.3 and 1.5 ± 0.4, respectively). Substitution with TLR4-deficient DCs abolished this effect. In a second in vivo approach, WT and biglycan-deficient mice were followed 2 wk after induction of myocardial infarction. WT mice demonstrated significantly greater myocardial T lymphocyte infiltration in comparison with biglycan-deficient animals. We concluded that the TLR2/4 ligand biglycan, a component of the myocardial matrix, may enhance Ag-specific T cell priming, potentially via MyD88 and TRIF, and stimulate autoimmune perimyocarditis.
  The Journal of Immunology 11/2011; 187(12):6217-26. · 5.79 Impact Factor
• Article: Screening and differential diagnosis of renal light chain-associated diseases.

  Jens Gerth, Anja Sachse, Martin Busch, Nico Illner, Lars-Olof Muegge, Hermann-Josef Gröne, Gunter Wolf
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  ABSTRACT: Renal involvement in the light chain-associated diseases multiple myeloma (MM), amyloidosis (AL) and monoclonal immune position disease (MIDD) is common and differential diagnosis usually requires renal biopsy. The aim of this study was to investigate if noninvasive methods are viable to identify and differentiate between the various types of kidney diseases. All patients with a light chain-associated disease admitted to our center from 1996 to 2008 were retrospectively evaluated. Renal biopsy data were correlated with proteinuria findings. Only the ratio of free κ/λ light chains showed a good sensitivity for myeloma cast nephropathy (MCN), AL and MIDD. The λ light chain was characteristic for AL, the κ light chain dominated in MIDD. Renal function at the time of diagnosis was worst in MIDD. MCN presented with a proteinuria of > 3.5 g/g creatinine. In contrast, a higher proteinuria was found in AL or MIDD. Whereas the κ/λ ratio in the urine was pathological for all three diseases, extremely high or low ratios indicated the presence of MCN. However, in AL or MIDD, the ratio was only moderately elevated. A noninvasive differentiation between MCN and other forms of renal light chain disease is possible.
  Kidney and Blood Pressure Research 11/2011; 35(2):120-8. · 1.46 Impact Factor
• Source

  Available from: Philipp Koch

  Article: A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat.

  Till Milde, Susanne Kleber, Andrey Korshunov, Hendrik Witt, Thomas Hielscher, Philipp Koch, Hans-Georg Kopp, Manfred Jugold, Hedwig E Deubzer, Ina Oehme, Marco Lodrini, Hermann-Josef Gröne, Axel Benner, Oliver Brüstle, Richard J Gilbertson, Andreas von Deimling, Andreas E Kulozik, Stefan M Pfister, Ana Martin-Villalba, Olaf Witt
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  ABSTRACT: Incompletely resectable ependymomas are associated with poor prognosis despite intensive radio- and chemotherapy. Novel treatments have been difficult to develop due to the lack of appropriate models. Here, we report on the generation of a high-risk cytogenetic group 3 and molecular group C ependymoma model (DKFZ-EP1NS) which is based on primary ependymoma cells obtained from a patient with metastatic disease. This model displays stem cell features such as self-renewal capacity, differentiation capacity, and specific marker expression. In vivo transplantation showed high tumorigenic potential of these cells, and xenografts phenotypically recapitulated the original tumor in a niche-dependent manner. DKFZ-EP1NS cells harbor transcriptome plasticity, enabling a shift from a neural stem cell-like program towards a profile of primary ependymoma tumor upon in vivo transplantation. Serial transplantation of DKFZ-EP1NS cells from orthotopic xenografts yielded secondary tumors in half the time compared with the initial transplantation. The cells were resistant to temozolomide, vincristine, and cisplatin, but responded to histone deacetylase inhibitor (HDACi) treatment at therapeutically achievable concentrations. In vitro treatment of DKFZ-EP1NS cells with the HDACi Vorinostat induced neuronal differentiation associated with loss of stem cell-specific properties. In summary, this is the first ependymoma model of a cytogenetic group 3 and molecular subgroup C ependymoma based on a human cell line with stem cell-like properties, which we used to demonstrate the differentiation-inducing therapeutic potential of HDACi.
  Acta Neuropathologica 08/2011; 122(5):637-50. · 9.32 Impact Factor
• Article: Forkhead factors regulate epithelial plasticity: impact on cancer progression.

  Alexander Feuerborn, Stefan Küffer, Hermann-Josef Gröne
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  ABSTRACT: Fox-factors modulate epithelial and mesenchymal cell fates in different stages during embryonic development. In the context of cancer they have mainly been described by their impact on cell proliferation, apoptosis and angiogenesis. Several studies have now pointed out that distinct members of the Forkhead transcription factor family are critically involved in modulating epithelial plasticity of carcinoma cells and thereby putatively enhance their metastatic and malignant capacity. Here we highlight these recent findings about new aspects of Fox-factor biology, which suggest that Fox-factors have a central role in the regulation of epithelial cell fates and cancer progression. A comprehensive molecular understanding of Fox-factors in this regard may provide potential new targets for therapeutic intervention.
  Cell cycle (Georgetown, Tex.) 08/2011; 10(15):2454-60. · 5.36 Impact Factor
• Article: Adipocyte-specific inactivation of Acyl-CoA synthetase fatty acid transport protein 4 (Fatp4) in mice causes adipose hypertrophy and alterations in metabolism of complex lipids under high fat diet.

  Lena-Solveig Lenz, Jana Marx, Walee Chamulitrat, Iris Kaiser, Hermann-Josef Gröne, Gerhard Liebisch, Gerd Schmitz, Christoph Elsing, Beate K Straub, Joachim Füllekrug, Wolfgang Stremmel, Thomas Herrmann
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  ABSTRACT: Fatp4 exhibits acyl-CoA synthetase activity and is thereby able to catalyze the activation of fatty acids for further metabolism. However, its actual function in most tissues remains unresolved, and its role in cellular fatty acid uptake is still controversial. To characterize Fatp4 functions in adipocytes in vivo, we generated a mouse line with adipocyte-specific inactivation of the Fatp4 gene (Fatp4(A-/-)). Under standard conditions mutant mice showed no phenotypical aberrance. Uptake of radiolabeled palmitic and lignoceric acid into adipose tissue of Fatp4(A-/-) mice was unchanged. When exposed to a diet enriched in long chain fatty acids, Fatp4(A-/-) mice gained more body weight compared with control mice, although they were not consuming more food. Pronounced obesity was accompanied by a thicker layer of subcutaneous fat and greater adipocyte circumference, although expression of genes involved in de novo lipogenesis was not changed. However, the increase in total fat mass was contrasted by a significant decrease in various phospholipids, sphingomyelin, and cholesteryl esters in adipocytes. Livers of Fatp4-deficient animals under a high fat diet exhibited a higher degree of fatty degeneration. Nonetheless, no evidence for changes in insulin sensitivity and adipose inflammation was found. In summary, the results of this study confirm that Fatp4 is not crucial for fatty acid uptake into adipocytes. Instead, under the condition of a diet enriched in long chain fatty acids, adipocyte-specific Fatp4 deficiency results in adipose hypertrophy and profound alterations in the metabolism of complex lipids.
  Journal of Biological Chemistry 07/2011; 286(41):35578-87. · 4.77 Impact Factor
• Article: Suppression of chronic damage in renal allografts by Liver X receptor (LXR) activation relevant contribution of macrophage LXRα.

  Eva Kiss, Zoran Popovic, Jens Bedke, Shijun Wang, Mahnaz Bonrouhi, Norbert Gretz, Paula Stettner, Daniel Teupser, Joachim Thiery, Stefan Porubsky, Judith Adams, Hermann-Josef Gröne
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  ABSTRACT: Liver X receptors (LXR)-α,β regulate intracellular cholesterol homeostasis and inhibit inflammatory gene expression. We studied the effects of the LXRα,β-agonist GW3965 on acute and chronic organ damage in the F344-LEW rat kidney transplantation model. In addition, to gain LXR isoform and cell-specific insights BALB/c kidneys were transplanted into mice with macrophage overexpression of LXRα (mLXRα-tg) and evaluated 7 and 42 days after transplantation. After 56 days GW3965 improved significantly function and morphology of rat kidney allografts by substantial reduction of mononuclear cell infiltrate and fibrosis; in vitro GW3965 reduced inflammatory activity of bone marrow-derived macrophages (BMDMs) and alloreactivity of T cells. Kidneys transplanted into mLXRα-tg mice were also protected from development of chronic allograft dysfunction. Similarly to GW3965-activated BMDMs, mLXRα-tg macrophages secreted significantly less monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β. Interestingly, 7 days after transplantation, when the total number of intragraft macrophages did not differ, evidently more arginase 1- and mannose receptor C type 1-positive cells were found in LXR rat and mice kidney allografts; in vitro both LXR activation by GW3965 and mLXRα overexpression accentuated the induction of alternative activation of BMDMs by IL-4/IL-13, suggesting an additional mechanism by LXRs to prevent graft damage. The results highlight the relevance of macrophage LXRα in allograft rejection and prevention of fibrosis.
  American Journal Of Pathology 07/2011; 179(1):92-103. · 4.89 Impact Factor