1. The mitogen-activated protein kinase p38α regulates tubular damage in murine anti-glomerular basement membrane nephritis
- Author
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Dirk Mielenz, Jochen Zwerina, Georg Schett, Christoph Daniel, Tobias Braun, Karlhans Endlich, Christian Hugo, Kerstin Amann, Peter Heeringa, Ralf R. Muller, Betty S. van der Veen, Groningen Kidney Center (GKC), and Translational Immunology Groningen (TRIGR)
- Subjects
Pathology ,Mouse ,RENAL INJURY ,Kidney Glomerulus ,CYTOSKELETON ,Signal transduction ,urologic and male genital diseases ,Biochemistry ,p38 Mitogen-Activated Protein Kinases ,ANGIOGENESIS ,Mice ,Molecular cell biology ,Glomerulonephritis ,Leukocytes ,Animal Management ,Mice, Knockout ,Multidisciplinary ,Enzyme Classes ,Podocytes ,Glomerular basement membrane ,Signaling cascades ,LOCALIZATION ,Agriculture ,Animal Models ,Enzymes ,DIFFERENTIATION ,medicine.anatomical_structure ,Kidney Tubules ,Nephrology ,Cytokines ,Medicine ,Tumor necrosis factor alpha ,medicine.symptom ,Inflammation Mediators ,CRESCENTIC GLOMERULONEPHRITIS ,Nephritis ,Transgenic Animals ,Research Article ,Vasculitis ,medicine.medical_specialty ,MAPK signaling cascades ,Phosphorylases ,Medizinische Fakultät -ohne weitere Spezifikation ,p38 mitogen-activated protein kinases ,Science ,Inflammation ,Biology ,Model Organisms ,INFLAMMATION ,Rheumatology ,medicine ,Renal fibrosis ,Animals ,ddc:610 ,Protein kinase A ,Autoantibodies ,urogenital system ,SELECTIVE INHIBITOR ,medicine.disease ,Molecular biology ,Enzyme Activation ,Disease Models, Animal ,Gene Expression Regulation ,P38 MAP KINASE ,CELLS ,Gene Deletion - Abstract
p38 mitogen-activated protein kinase (MAPK) is thought to play a central role in acute and chronic inflammatory responses. Whether p38MAPK plays a pathogenic role in crescentic GN (GN) and which of its four isoforms is preferentially involved in kidney inflammation is not definitely known. We thus examined expression and activation of p38MAPK isoforms during antiglomerular basement membrane (GBM) nephritis. Therefore, p38 alpha conditional knockout mice (MxCre-p38 alpha(Delta/Delta)) were used to examine the role of p38 alpha in anti-GBM induced nephritis. Both wild type and MxCre-p38 alpha(Delta/Delta) mice developed acute renal failure over time. Histological examinations revealed a reduced monocyte influx and less tubular damage in MxCre-p38 alpha(Delta/Delta) mice, whereas glomerular crescent formation and renal fibrosis was similar. Likewise, the levels of pro-and anti-inflammatory cytokines such as TNF, IL-1 and IL-10 were similar, but IL-8 was even up-regulated in MxCre-p38 alpha(Delta/Delta) mice. In contrast, we could detect strong down-regulation of chemotactic cytokines such as CCL-2, -5 and -7, in the kidneys of MxCre-p38 alpha(Delta/Delta) mice. In conclusion, p38 alpha is the primary p38MAPK isoform expressed in anti-GBM nephritis and selectively affects inflammatory cell influx and tubular damage. Full protection from nephritis is however not achieved as renal failure and structural damage still occurs.
- Published
- 2013