Degradation of glomerular heparan sulfate by heparanase.
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Annotation
RU Radboud Universiteit Nijmegen, 31 januari 2008
Promotor : Berden, J.H.M.
Co-promotores : Vlag, J. van der, Kuppevelt, A.H.M.S.M. van
Publication type
Dissertation

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Organization
Nephrology
Subject
NCMLS 1: Immunity, infection and tissue repair; UMCN 5.4: Renal disordersAbstract
We have focused our research on the role of heparanase (HPSE) in the degradation of glomerular HS with emphasis on DNP. We mainly focused on the analysis of kidney biopsies of patients with DNP. In patients with overt DNP we confirmed the decrease of GBM HS (-50%) and tubular HS (-60%) expression, which was associated with a 4-fold increase in HPSE expression. Decrease of HS was correlated (r=-0.56 p<0.001) with increased HPSE expression. Similar findings were found in experimental STZ-induced DNP. The specificity of HS cleavage by HPSE was assessed in a different cohort of patients with DNP. Using a panel of anti-HS antibodies with different specificities, we found that HPSE degrades specific sulfated HS domains but not unmodified HS domains. This was also observed in kidneys of transgenic HPSE-overexpressing mice and when normal kidney sections were exposed in vitro to recombinant active HPSE. Next, we evaluated the urinary activity of HPSE in T1D and T2D patients compared to patients with membranous glomerulopathy (MGP) and healthy controls. The majority of the diabetic patients showed an increased urinary HPSE activity, which correlated with proteinuria. This was not specific for diabetes since also in MGP urinary HPSE activity was increased. Patients treated with inhibitors of the RAAS had lower HPSE activity than patients treated with other antihypertensive drugs, but higher activity than diabetes patients without hypertension. The regulation of HPSE expression was evaluated in adriamycin nephropathy, in which a comparable increase of HPSE expression was found. Treatment with angiotensin II receptor 1 blockers reduced HPSE expression and normalized HS expression. Similar results were found for ACE inhibitors and aldosterone receptor blockers. Angiotensin II, aldosterone and reactive oxygen species could in vitro induce HPSE expression in cultured podocytes
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- Dissertations [12265]
- Electronic publications [101091]
- Faculty of Medical Sciences [80072]
- Open Access publications [69755]
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