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      Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice

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          Abstract

          Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal involvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential involvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mechanism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions. The specific heparanase inhibitor SST0001 markedly decreased the extent of albuminuria and renal damage in mouse models of DN. Our results collectively underscore the crucial role of heparanase in the pathogenesis of DN and its potential as a highly relevant target for therapeutic interventions in patients with DN.

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          The role of inflammatory cytokines in diabetic nephropathy.

          Juan F. Navarro-González, Carmen Mora-Fernández (2008)
          Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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            Mouse models of diabetic nephropathy.

            Matthew Breyer, Erwin B Bottinger, Frank C Brosius … (2005)
            Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.
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              Macrophage accumulation in human progressive diabetic nephropathy.

              Phong Nguyen, Matthew P. Hill, Wei Mu … (2006)
              Diabetic nephropathy is a major global health problem. Progression to renal failure is common; however, the mechanisms are unknown. Experimental models suggest a role for macrophages. Therefore, macrophage accumulation and its relationship to the subsequent clinical course were studied. A retrospective study of baseline histology and the subsequent clinical course over at least 5 years involving 20 consecutive patients with a histological and clinical diagnosis of diabetic nephropathy was performed. The relationship between macrophage accumulation in renal biopsy tissue (KP-1/anti-CD68+ cells), baseline measures of known predictors of progression (proteinuria, tubulointerstitial damage, myofibroblast accumulation) and progression over 5 years (plot of reciprocal of serum creatinine) was quantified. Accumulation of macrophages was apparent in the glomeruli (2.8 + 0.7/gcs vs 1.0 + 0.2 for normals, P = not significant) and interstitium (296.9 + 63.3/mm(2) vs 19.0 + 1.3/mm(2) for normals, P = 0.002) of patients with diabetic nephropathy. Glomerular macrophage number correlated with baseline serum creatinine (r = 0.548, P = 0.012) but not with progression of renal failure as glomerular macrophages were prevalent in early, but not advanced diabetic nephropathy. Interstitial macrophage accumulation correlated strongly with serum creatinine (r = 0.649, P = 0.002), proteinuria (r = 0.779, P < 0.0001), interstitial fibrosis (r = 0.774, P < 0.0001) and inversely with the slope of 1/serum creatinine (r = -0.531, P = 0.023). Macrophages accumulate within glomeruli and the interstitium in diabetic nephropathy and the intensity of the interstitial infiltrate is proportional to the rate of subsequent decline in renal function. These human data support animal studies that suggest a pathogenic role for the macrophage in diabetic nephropathy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes
                Journal ID (hwp): diabetes
                Journal ID (pmc): diabetes
                Journal ID (publisher-id): Diabetes
                Title: Diabetes
                Publisher: American Diabetes Association
                ISSN (Print): 0012-1797
                ISSN (Electronic): 1939-327X
                Publication date (Print): January 2012
                Publication date (Electronic): 12 December 2011
                Volume: 61
                Issue: 1
                Pages: 208-216
                Affiliations
                [1] 1Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [2] 2Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [3] 3Nephrology Research Laboratory, Department of Nephrology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
                [4] 4Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel
                [5] 5Department of Matrix Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
                [6] 6Oncology Area Research and Development, Sigma-Tau S.p.A., Rome, Italy
                [7] 7Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
                Author notes
                Corresponding author: Michael Elkin, melkin@ 123456hadassah.org.il , or Israel Vlodavsky, vlodavsk@ 123456cc.huji.ac.il .

                N.G. and R.G. contributed equally to this work.

                Article
                Publisher ID: 1024
                DOI: 10.2337/db11-1024
                PMC ID: 3237641
                PubMed ID: 22106160
                SO-VID: fee33f21-5aed-4c34-befd-e620a0e9e7d2
                Copyright © © 2012 by the American Diabetes Association.
                License:

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                Date received : 31 July 2011
                Date accepted : 05 October 2011
                Categories
                Subject: Complications

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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