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      Deterioration of glomerular endothelial surface layer induced by oxidative stress is implicated in altered permeability of macromolecules in Zucker fatty rats

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          Abstract

          Aims/hypothesis

          The glomerular endothelial layer is coated by the endothelial surface layer (ESL), which is suggested to play a role in regulation of the permselectivity of macromolecules. Production of heparanase, a degrading enzyme of the ESL, is induced by reactive oxygen species (ROS). We hypothesised that oxidative stress could cause deterioration of the glomerular ESL by induction of heparanase, resulting in increased glomerular permeability.

          Methods

          Male Zucker fatty (ZF) rats with albuminuria and Zucker lean (ZL) rats were used in this study. Some of the ZF rats were treated with the angiotensin II receptor blocker, irbesartan. We determined the amount of ESL by wheat germ agglutinin staining and heparan sulphate proteoglycan production by western blot analysis. Glomerular hyperfiltration of macromolecules was visualised using in vivo microscopy. We used 2′,7′-dichlorofluorescein diacetate-derived chemiluminescence staining to assess ROS production, and heparanase production and expression were determined by western blot analysis and quantitative real-time polymerase chain reaction respectively.

          Results

          By 18 weeks of age, ZF rats had developed albuminuria. The glomerular endothelial cell glycocalyx was significantly decreased in ZF compared with ZL rats. Glomerular filtration and the permeability of macromolecules were increased in ZF, but not in ZL rats. Glomerular ROS and heparanase production were significantly increased in ZF compared with ZL rats. These changes in ZF rats were reversed by irbesartan treatment.

          Conclusions/interpretation

          Increased oxidative stress induces glomerular ESL deterioration in part through increased heparanase levels, resulting in exacerbation of glomerular permselectivity and development of albuminuria.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00125-010-1810-0) contains supplementary material, which is available to authorised users.

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          Most cited references37

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          Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.

          Hans Hillege, Vaclav Fidler, Gilles F. H. Diercks … (2002)
          For the general population, the clinical relevance of an increased urinary albumin excretion rate is still debated. Therefore, we examined the relationship between urinary albumin excretion and all-cause mortality and mortality caused by cardiovascular (CV) disease and non-CV disease in the general population. In the period 1997 to 1998, all inhabitants of the city of Groningen, the Netherlands, aged between 28 and 75 years (n=85 421) were sent a postal questionnaire collecting information about risk factors for CV disease and CV morbidity and a vial to collect an early morning urine sample for measurement of urinary albumin concentration (UAC). The vital status of the cohort was subsequently obtained from the municipal register, and the cause of death was obtained from the Central Bureau of Statistics. Of these 85 421 subjects, 40 856 (47.8%) responded, and 40 548 could be included in the analysis. During a median follow-up period of 961 days (maximum 1139 days), 516 deaths with known cause were recorded. We found a positive dose-response relationship between increasing UAC and mortality. A higher UAC increased the risk of both CV and non-CV death after adjustment for other well-recognized CV risk factors, with the increase being significantly higher for CV mortality than for non-CV mortality (P=0.014). A 2-fold increase in UAC was associated with a relative risk of 1.29 for CV mortality (95% CI 1.18 to 1.40) and 1.12 (95% CI 1.04 to 1.21) for non-CV mortality. Urinary albumin excretion is a predictor of all-cause mortality in the general population. The excess risk was more attributable to death from CV causes, independent of the effects of other CV risk factors, and the relationship was already apparent at levels of albuminuria currently considered to be normal.
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            Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study.

            Johan Ärnlöv, Jane C Evans, James Meigs … (2005)
            Data are limited with regard to the relations of low-grade albuminuria (below the microalbuminuria threshold) and incidence of cardiovascular disease (CVD) events in nondiabetic, nonhypertensive individuals. We examined the association of urinary albumin excretion (spot urine albumin indexed to creatinine [UACR]) and the incidence of CVD events and all-cause mortality in 1568 nonhypertensive, nondiabetic Framingham Offspring Study participants (mean age, 55 years; 58% women) free of CVD. On follow-up (median, 6 years), 54 participants (20 women) developed a first CVD event, and 49 (19 women) died. After adjustment for established risk factors, increasing UACR was associated with greater risk of CVD (hazards ratio [HR] per SD increment in log UACR, 1.36; 95% CI, 1.00 to 1.87) and death (HR per SD increment in log UACR, 1.55; 95% CI, 1.10 to 2.20). Participants with UACR greater than or equal to the sex-specific median (> or =3.9 microg/mg for men, > or =7.5 microg/mg for women) experienced a nearly 3-fold risk of CVD (adjusted HR, 2.92; 95% CI, 1.57 to 5.44; P<0.001) and a borderline significantly increased risk of death (adjusted HR, 1.75; 95% CI, 0.95 to 3.22; P=0.08) compared with those with UACR below the median. The increased CVD risk associated with UACR at or above the median remained robust in analyses restricted to individuals without microalbuminuria (n=1470) and in subgroups with intermediate (n=1469) and low (n=1186) pretest probabilities of CVD. In our community-based sample of middle-aged nonhypertensive, nondiabetic individuals, low levels of urinary albumin excretion well below the current microalbuminuria threshold predicted the development of CVD. Our observations add to the growing body of evidence that challenges the notion that UACR <30 microg/mg indicates "normal" albumin excretion.
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              Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface.

              Alina A. Constantinescu, Hans Vink, J A Spaan (2003)
              A thick endothelial glycocalyx provides the endothelial surface with a nonadherent shield. Oxidized LDL (Ox-LDL) degrades the endothelial glycocalyx. We hypothesized that glycocalyx degradation stimulates leukocyte-endothelial cell adhesion, whereas intravascular supplementation with sulfated polysaccharides reconstitutes the endothelial glycocalyx and attenuates Ox-LDL-induced leukocyte-endothelial cell adhesion. Degradation of the endothelial glycocalyx by local microinjection of heparitinase (10 to 50 U/mL) into mouse cremaster venules dose-dependently increased the number of adherent leukocytes. Systemic administration of Ox-LDL (0.4 mg/100 g body weight) induced 10.1+/-0.9 adherent leukocytes/100 microm at 60 minutes. In the venules perfused with 500-kDa dextran sulfate (1 mg/mL), the number of adherent leukocytes at 60 minutes after Ox-LDL bolus application was not influenced (9.2+/-1.0 leukocytes/100 microm). However, the venules locally perfused with heparan sulfate (10 mg/mL) or heparin (1 mg/mL) displayed a significantly lower number of adherent leukocytes induced by Ox-LDL: 5.1+/-0.7 and 5.4+/-0.9 leukocytes/100 microm, respectively (P<0.05). Fluorescently labeled heparan sulfate and heparin, but not dextran sulfate, attached to the venule luminal surface after Ox-LDL administration. Endothelial glycocalyx degradation stimulates leukocyte immobilization at the endothelial surface. Circulating heparan sulfate and heparin attach to the venule wall and attenuate Ox-LDL-induced leukocyte immobilization.
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                Author and article information

                Contributors
                : msatoh@med.kawasaki-m.ac.jp
                Journal
                Journal ID (nlm-ta): Diabetologia
                Title: Diabetologia
                Publisher: Springer-Verlag (Berlin/Heidelberg )
                ISSN (Print): 0012-186X
                ISSN (Electronic): 1432-0428
                Publication date (Electronic): 6 June 2010
                Publication date PMC-release: 6 June 2010
                Publication date (Print): September 2010
                Volume: 53
                Issue: 9
                Pages: 2056-2065
                Affiliations
                Division of Nephrology and Hypertension, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192 Japan
                Article
                Publisher ID: 1810
                DOI: 10.1007/s00125-010-1810-0
                PMC ID: 2910881
                PubMed ID: 20526760
                SO-VID: 21671bc1-3a9f-4308-a615-690571e29927
                Copyright © © The Author(s) 2010
                History
                Date received : 25 February 2010
                Date accepted : 6 May 2010
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Springer-Verlag 2010

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: vascular regulation,haemodynamics,reactive oxygen species,permeability,glomerulus,zucker fatty rat,endothelial surface layer,glycocalyx,endothelial cell
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: vascular regulation, haemodynamics, reactive oxygen species, permeability, glomerulus, zucker fatty rat, endothelial surface layer, glycocalyx, endothelial cell

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