Showing papers by "Hermann Josef Gröne published in 2013"
TL;DR: Upregulation of miR-193a provides a new pathogenic mechanism for FSGS and is a potential therapeutic target, found in isolated glomeruli from individuals with FSGS compared to normal kidneys or individuals with other glomerular diseases.
Abstract: Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. We report that transgenic expression of the microRNA miR-193a in mice rapidly induces FSGS with extensive podocyte foot process effacement. Mechanistically, miR-193a inhibits the expression of the Wilms' tumor protein (WT1), a transcription factor and master regulator of podocyte differentiation and homeostasis. Decreased expression levels of WT1 lead to downregulation of its target genes PODXL (podocalyxin) and NPHS1 (nephrin), as well as several other genes crucial for the architecture of podocytes, initiating a catastrophic collapse of the entire podocyte-stabilizing system. We found upregulation of miR-193a in isolated glomeruli from individuals with FSGS compared to normal kidneys or individuals with other glomerular diseases. Thus, upregulation of miR-193a provides a new pathogenic mechanism for FSGS and is a potential therapeutic target.
184 citations
TL;DR: It is demonstrated that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identifies this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival.
Abstract: Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
173 citations
TL;DR: Local PTX3 release from a subpopulation of intrarenal mononuclear phagocytes or delayedPTX3 treatment limits postischemic renal inflammation, whereas Ptx3 loss-of-function mutations predispose to postischenic acute kidney injury and subsequent chronic kidney disease.
80 citations
TL;DR: It is demonstrated that IRP deficiency impairs iron absorption and promotes mucosal iron retention via a ferritin-mediated "mucosal block" and defines a basal set point for iron absorption upon which IRP-independent systemic regulatory inputs are overlaid.
79 citations
TL;DR: 1-O-acylceramides are described as a new class of epidermal Cers in humans and mice and proposed to be synthesized at endoplasmic reticulum-related sites for water barrier homeostasis.
61 citations
TL;DR: Gene expression profiling of Ugcg-mutant skin revealed a subset of differentially expressed genes involved in lipid signaling and epidermal differentiation/proliferation, correlating to human skin diseases such as psoriasis and atopic dermatitis.
Abstract: Skin barrier function is primarily assigned to the outer epidermal layer, the stratum corneum (SC), mainly composed of corneocytes and lipid-enriched extracellular matrix. Epidermal ceramides (Cers) are essential barrier lipids, containing ultra-long-chain (ULC) fatty acids (FAs) with a unique ω-hydroxy group, which is necessary for binding to corneocyte proteins. In the SC, Cers are believed to derive from glucosylated intermediates, namely glucosylceramides (GlcCers), as surmised from human Gaucher's disease and related mouse models. Tamoxifen (TAM)-induced deletion of the endogenous GlcCer-synthesizing enzyme UDP-glucose:ceramide glucosyltransferase (UGCG) in keratin K14-positive cells resulted in epidermal GlcCer depletion. Although free extractable Cers were elevated in total epidermis and as well in SC, protein-bound Cers decreased significantly in Ugcg(f/fK14CreERT2) mice, indicating glucosylation to be required for regular Cer processing as well as arrangement and extrusion of lipid lamellae. The almost complete loss of protein-bound Cers led to a disruption of the water permeability barrier (WPB). UGCG-deficient mice developed an ichthyosis-like skin phenotype marked by impaired keratinocyte differentiation associated with delayed wound healing. Gene expression profiling of Ugcg-mutant skin revealed a subset of differentially expressed genes involved in lipid signaling and epidermal differentiation/proliferation, correlating to human skin diseases such as psoriasis and atopic dermatitis. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), a Cer-sensitive transcription factor was identified as potential mediator of the altered gene sets.
47 citations
TL;DR: S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart.
Abstract: Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE−/− mice by 50% (p < 0001) This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-κB family in wild type (WT) and RAGE−/− mouse endothelial cells Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-κB activation in RAGE−/−, but not in WT cells The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE−/− animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p < 0001) Experiments in ALCAM−/− animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa Consistently, ALCAM−/− mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM−/− RAGE−/− double-knockout mice show a 27% reduction in DTH reaction Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart
42 citations
TL;DR: GAS1 is a novel endogenous inhibitor of glomerular mesangial cell proliferation and may be a novel therapeutic target in mesangioproliferative glomerulonephritis diseases.
25 citations
TL;DR: The effect of on-line highflux hemofiltration versus low-flux hemodialysis on mortality in chronic kidney failure in patients at different stages of chronic kidney disease is studied.
Abstract: membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol 2009; 20: 645–654 21. Santoro A, Mancini E, Bolzani R et al. The effect of on-line highflux hemofiltration versus low-flux hemodialysis on mortality in chronic kidney failure: a small randomized controlled trial. Am J Kidney Dis 2008; 52: 507–518 22. Gutzwiller JP, Schneditz D, Huber AR et al. Increasing blood flow increases kt/V(urea) and potassium removal but fails to improve phosphate removal. Clin Nephrol 2003; 59: 130–136 23. Bleyer AJ, Hartman J, Brannon PC et al. Characteristics of sudden death in hemodialysis patients. Kidney Int 2006; 69: 2268–2273 24. Eloot S, Torremans A, De Smet R et al. Kinetic behavior of urea is different from that of other water-soluble compounds: the case of the guanidino compounds. Kidney Int 2005; 67: 1566–1575 25. Jourde-Chiche N, Dou L, Cerini C et al. Protein-bound toxins— update 2009. Semin Dial 2009; 22: 334–339 26. Barreto FC, Barreto DV, Liabeuf S et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 2009; 4: 1551–1558 27. Liabeuf S, Barreto DV, Barreto FC et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant 2010; 25: 1183–1191 28. Sirich TL, Luo FJ, Plummer NS et al. Selectively increasing the clearance of protein-bound uremic solutes. Nephrol Dial Transplant 2012; 27: 1574–1579 29. De Smet R, Dhondt A, Eloot S et al. Effect of the super-flux cellulose triacetate dialyser membrane on the removal of nonprotein-bound and protein-bound uraemic solutes. Nephrol Dial Transplant 2007; 22: 2006–2012
22 citations
TL;DR: A review of experimental data and earlier case reports suggests a pathogenic role of recombinant IFN in some autoimmune diseases, especially those with the potency to induce systemic lupus erythematosus-like syndromes.
21 citations
TL;DR: Comt has been confirmed to be the first reported modifier gene for PKD and tolcapone offers a promising drug for treating PKD.
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. Results Comt 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.
TL;DR: In this article, the histopathologischen Veranderungen bei Lupusglomerulonephritis unter Einschluss von Differenzial Diagnosen are discussed.
Abstract: Dieser Artikel beschreibt die histopathologischen Veranderungen bei Lupusglomerulonephritis unter Einschluss von Differenzialdiagnosen. Die Lupusnephritis ist hauptsachlich eine Erkrankung des Glomerulus; pra- und postglomerulare Gefase und das Interstitium konnen betroffen sein. Gemeinsam mit einer intensiven klinischen und serologischen Untersuchung kann mit Hilfe der Kombination aus lichtmikroskopischen, immunhistologischen und elektronenmikroskopischen Untersuchungen die Diagnose einer Lupusnephritis gestellt werden. Die Angabe einer international anerkannten Klassifikation der Lupusnephritis sowie die Angabe des glomerularen Aktivitatsindex und des tubulointerstitiellen Chronizitatsindex sind hilfreich bei der Abschatzung der Therapie und Prognose. Ein semiquantitativer Score der interstitiellen Fibrose und der tubularen Atrophie ist ein verlasslicher prognostischer Parameter. Die Differenzialdiagnose der Lupusglomerulonephritis schliest Patienten mit thrombotischer Mikroangiopathie, HIV-Infektion, membranoproliferativer Glomerulonephritis und IgA-Nephritis ein.