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      Enhanced Hyaluronan Synthesis in the MRL- Fas lpr Kidney: Role of Cytokines


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          Background/Aim: Pathological accumulation of the extracellular matrix component hyaluronan (HA) occurs in the kidney cortex in immune-system mediated tissue injury. The purpose of the present study was to examine the pattern of HA deposition and the mechanisms of HA synthesis in the MRL- Fas<sup>lpr</sup> mouse model of lupus nephritis. Methods: Kidneys from normal and autoimmune mice were examined for HA content by immunofluorescence staining. Steady state mRNA levels for key enzymes involved in HA synthesis – uridine diphosphate-glucose dehydrogenase (UDPGDH) and HA synthases (HAS) 1, 2 and 3 – were assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Using cultured mouse tubular epithelial cells, the regulation of the HA production in vitro in response to tumor necrosis factor alpha and interferon gamma was also examined. Results: By immunofluorescence staining, large amounts of HA were detected in the cortical interstitium of MRL- Fas<sup>lpr</sup> mice with autoimmune renal injury, but not in congenic MRL-++ mice. By RT-PCR the presence of transcripts for several genes involved in the synthesis of HA in normal and autoimmune kidneys could be demonstrated, including mRNA for UDPGDH and HAS1 and HAS2, but not for HAS3. Except for HAS2, steady state mRNA levels for these enzymes did not correlate with disease activity. Analyzing a kidney tubular epithelial cell line in vitro, it was found that tumor necrosis factor alpha and interferon gamma, and particularly the combination of these two cytokines, markedly enhanced the synthesis of HA. The expression of HAS2 mRNA was also enhanced in response to cytokine treatment. Conclusions: HA deposition is prominent in MRL- Fas<sup>lpr</sup> mice with renal disease and could be mediated by local synthesis through HAS1 and HAS2. We hypothesize that the enhanced synthesis of HA could be promoted by proinflammatory cytokines in vivo. The functional significance of HA accumulation in autoimmune renal injury remains to be determined.

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          Most cited references7

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          Hyaluronan Synthases

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            Characterization and molecular evolution of a vertebrate hyaluronan synthase gene family.

            The three mammalian hyaluronan synthase (HAS) genes and the related Xenopus laevis gene, DG42, belong to a larger evolutionarily conserved vertebrate HAS gene family. We have characterized additional vertebrate HAS genes from chicken (chas2 and chas3) and Xenopus (xhas2, xhas3, and a unique Xenopus HAS-related sequence, xHAS-rs). Genomic structure analyses demonstrated that all vertebrate HAS genes share at least one exon-intron boundary, suggesting that they evolved from a common ancestral gene. Furthermore, the Has2 and Has3 genes are identical in structure, suggesting that they arose by a gene duplication event early in vertebrate evolution. Significantly, similarities in the genomic structures of the mouse Has1 and Xenopus DG42 genes strongly suggest that they are orthologues. Northern analyses revealed a similar temporal expression pattern of HAS genes in developing mouse and Xenopus embryos. Expression of mouse Has2, Has3, and Xenopus Has1 (DG42) led to hyaluronan biosynthesis in transfected mammalian cells. However, only mouse Has2 and Has3 expressing cells formed significant hyaluronan-dependent pericellular coats in culture, implying both functional similarities and differences among vertebrate HAS enzymes. We propose that vertebrate hyaluronan biosynthesis is regulated by a comparatively ancient gene family that has arisen by sequential gene duplication and divergence.
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              Proteoglycans on endothelial cells present adhesion-inducing cytokines to leukocytes.

              Leukocyte recruitment from the blood circulation into tissue is essential for effective immune responses, and is, consequently, carefully regulated. In this article Yoshiya Tanaka and co-workers describe a model in which proteoglycans on the luminal surface of endothelium capture pro-adhesive cytokines. These cytokines provide the adhesion-inducing signal to particular leukocyte subsets which initiates their transmigration.

                Author and article information

                S. Karger AG
                September 1999
                31 August 1999
                : 83
                : 1
                : 66-73
                aPhysiological Institute, University Zürich-Irchel, Zürich, and bDepartment of Anesthesiology and cDivision of Nephrology, University Hospital, Zürich, Switzerland
                45475 Nephron 1999;83:66–73
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 2, References: 32, Pages: 8
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/45475
                Self URI (text/html): https://www.karger.com/Article/FullText/45475
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                Hyaluronan,CD44,Lupus nephritis,Mouse
                Cardiovascular Medicine, Nephrology
                Hyaluronan, CD44, Lupus nephritis, Mouse


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