Phenotypic Expression of ADAMTS13 in Glomerular Endothelial Cells

Background: ADAMTS13 is the physiological von Willebrand factor (VWF)-cleaving protease. The aim of this study was to examine ADAMTS13 expression in kidneys from ADAMTS13 wild-type (Adamts13+/+) and deficient (Adamts13-/-) mice and to investigate the expression pattern and bioactivity in human glomerular endothelial cells. Methodology/Principal Findings: Immunohistochemistry was performed on kidney sections from ADAMTS13 wild-type and ADAMTS13-deficient mice. Phenotypic differences were examined by ultramorphology. ADAMTS13 expression in human glomerular endothelial cells and dermal microvascular endothelial cells was investigated by real-time PCR, flow cytometry, immunofluorescence and immunoblotting. VWF cleavage was demonstrated by multimer structure analysis and immunoblotting. ADAMTS13 was demonstrated in glomerular endothelial cells in Adamts13+/+ mice but no staining was visible in tissue from Adamts13-/- mice. Thickening of glomerular capillaries with platelet deposition on the vessel wall was detected in Adamts13-/- mice. ADAMTS13 mRNA and protein were detected in both human endothelial cells and the protease was secreted. ADAMTS13 activity was demonstrated in glomerular endothelial cells as cleavage of VWF. Conclusions/Significance: Glomerular endothelial cells express and secrete ADAMTS13. The proteolytic activity could have a protective effect preventing deposition of platelets along capillary lumina under the conditions of high shear stress present in glomerular capillaries. © 2011 Tati et al.published_or_final_versio

Angiogenesis and chronic kidney disease

The number of patients requiring renal replacement therapy due to end-stage renal disease (ESRD) is increasing worldwide. The prevalence of chronic kidney disease (CKD), and the importance of CKD as a risk factor in development of ESRD and in complicating cardiovascular disease (CVD) have been confirmed. In recent years, the involvement of angiogenesis-related factors in the progression of CKD has been studied, and the potential therapeutic effects on CKD of modulating these factors have been identified. Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, in maintenance of the glomerular capillary structure and filtration barrier, and in the renal repair process after injury. VEGF-A is also involved in the development of early diabetic nephropathy, demonstrated by the therapeutic effects of anti-VEGF-A antibody. Angiopoietin (Ang)-1 induces the maturation of newly formed blood vessels, and the therapeutic effects of Ang-1 in diabetic nephropathy have been described. In experimental models of diabetic nephropathy, the therapeutic effects of angiogenesis inhibitors, including angiostatin, endostatin and tumstatin peptides, the isocoumarin NM-3, and vasohibin-1, have been reported

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan

Interferon-β reduces proteinuria in experimental glomerulonephritis

Interferon-β (IFN-β) is a multifunctional cytokine with immunomodulatory properties. We examined the effect of IFN-β in three separate rat models of glomerular injury and in cultured human glomerular endothelial cells and podocytes. In nephrotoxic nephritis in WKY rats, recombinant rat IFN-β started either at induction or after establishment of disease significantly reduced 24-h proteinuria by up to 73% and 51%, respectively, but did not affect serum creatinine. There was a slight reduction in numbers of glomerular macrophages, but no difference in glomerular or tubulointerstitial scarring. In Thy-1 nephritis in Lewis rats, IFN-β started at induction of disease reduced proteinuria by up to 66% with no effect on numbers of glomerular macrophages, but a reduced number of proliferating cells. In puromycin nephropathy in Wistar rats, IFN-β started at induction of disease reduced proteinuria by up to 93%, but had no effect on glomerular histology. In cultured cells, human IFN-β-1a had a dramatic effect on barrier properties, increasing electrical resistance across monolayers of either glomerular endothelial cells or podocytes and decreasing trans-monolayer passage of albumin. In conclusion, these results show that IFN-β reduces proteinuria in three different rat models of glomerular injury and that its anti-proteinuric action may result from direct effects on cells that comprise the glomerular filtration barrier. These data indicate that IFN-β may have potential as a therapeutic agent in proteinuric renal disease. Copyright © 2007 by the American Society of Nephrology.link_to_subscribed_fulltex

Effects of terrestrial isopods on the decomposition of woodland leaf litter

The indirect contribution terrestrial isopods make to decomposition processes by stimulating microbial activites has been quantified in laboratory experiments. The extent to which microbial metabolism is enhanced as a result of the passage of Betula pendula leaf litter through the alimentary system of isopods was measured for both freshly fallen and decayed leaves. Faeces derived from 1 g freshly fallen litter lost 75 mg g-1 D.W. more than did intact leaves, as a result of enhanced microbial metabolism. Faeces derived from 1 g of previously decayed leaves, which were shown to be the preferred food of isopods, lost only 17.5 mg g-1 D.W. more than intact decaying leaves. The isopod's direct contribution to soil metabolism was calculated to be 151 mg and 138 mg g-1 litter ingested when fed on freshly fallen and decayed leaves respectively. It is concluded that the physical and chemical changes in the leaf substrate which result from fragmentation and digestion by isopods do not necessarily accelerate the subsequent decomposition of the litter very significantly. Fungal propagule density was 3.2x and 3.6x higher in faeces derived from freshly fallen and decayed leaves respectively than in the intact litter. Numbers of viable bacteria were correspondingly 126x and 34x higher in faeces than in the freshly fallen and the decayed leaves. Levels of microbial inhibitors were lower in the faeces than in the leaves but levels of free amino acids stayed higher for longer in the faeces than they did in intact litter. In the field the physical removal of litter by the soil macrofauna from surface to deeper and moister microsites may be the most important indirect contribution that they make to decomposition processes