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      Inhibiting the urokinase‐type plasminogen activator receptor system recovers STZ‐induced diabetic nephropathy

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          Abstract

          The urokinase‐type plasminogen activator ( uPA) receptor ( uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR ‐(s)u PAR‐ from circulation) is to regulate podocyte function through αvβ3 integrin/Rac‐1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors ( FPRs) can improve kidney lesions in a rat model of streptozotocin ( STZ)‐induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac‐1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ‐induced up‐regulation of uPA levels and activity, while uPAR on podocytes and (s)u PAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac‐1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen‐plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/ uPAR system as a promising target for the development of novel uPAR‐targeting approaches.

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          Modification of kidney barrier function by the urokinase receptor.

          Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of alphavbeta3 integrin. Mice lacking uPAR (Plaur-/-) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active beta3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate alphavbeta3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of alphavbeta3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.
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            The cell biology of renal filtration

            The function of the kidney, filtering blood and concentrating metabolic waste into urine, takes place in an intricate and functionally elegant structure called the renal glomerulus. Normal glomerular function retains circulating cells and valuable macromolecular components of plasma in blood, resulting in urine with just trace amounts of proteins. Endothelial cells of glomerular capillaries, the podocytes wrapped around them, and the fused extracellular matrix these cells form altogether comprise the glomerular filtration barrier, a dynamic and highly selective filter that sieves on the basis of molecular size and electrical charge. Current understanding of the structural organization and the cellular and molecular basis of renal filtration draws from studies of human glomerular diseases and animal models of glomerular dysfunction.
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              Diabetic nephropathy and extracellular matrix.

              Diabetic nephropathy (DN) is a serious complication in diabetes. Major typical morphological changes are the result of changes in the extracellular matrix (ECM). Thus, basement membranes are thickened and the glomerular mesangial matrix and the tubulointerstitial space are expanded, due to increased amounts of ECM. One important ECM component, the proteoglycans (PGs), shows a more complex pattern of changes in DN. PGs in basement membranes are decreased but increased in the mesangium and the tubulointerstitial space. The amounts and structures of heparan sulfate chains are changed, and such changes affect levels of growth factors regulating cell proliferation and ECM synthesis, with cell attachment affecting endothelial cells and podocytes. Enzymes modulating heparan sulfate structures, such as heparanase and sulfatases, are implicated in DN. Other enzyme classes also modulate ECM proteins and PGs, such as matrix metalloproteinases (MMPs) and serine proteases, such as plasminogen activator, as well as their corresponding inhibitors. The levels of these enzymes and inhibitors are changed in plasma and in the kidneys in DN. Several growth factors, signaling pathways, and hyperglycemia per se affect ECM synthesis and turnover in DN. Whether ECM components can be used as markers for early kidney changes is an important research topic, whereas at present, the clinical use remains to be established.
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                Author and article information

                Contributors
                massimo.dalmonte@unipi.it
                paola.bagnoli@unipi.it
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                13 November 2018
                February 2019
                : 23
                : 2 ( doiID: 10.1111/jcmm.2019.23.issue-2 )
                : 1034-1049
                Affiliations
                [ 1 ] Department of Biology University of Pisa Pisa Italy
                [ 2 ] Department of Sciences University of Basilicata Potenza Italy
                [ 3 ] Department of Biosciences, Biotechnologies and Biopharmaceutics University of Bari Bari Italy
                [ 4 ] Department of Experimental and Clinical Medicine University of Firenze Firenze Italy
                [ 5 ] Department of Experimental Medicine Second University of Napoli Napoli Italy
                [ 6 ] Department of Chemical Sciences University of Napoli Federico II Napoli Italy
                [ 7 ] Institute of Biomembranes and Bioenergetics National Research Council Bari Italy
                Author notes
                [*] [* ] Correspondence

                Massimo Dal Monte and Paola Bagnoli, Department of Biology, University of Pisa, Pisa, Italy.

                Emails: massimo.dalmonte@ 123456unipi.it and paola.bagnoli@ 123456unipi.it

                Author information
                http://orcid.org/0000-0002-5181-4456
                Article
                JCMM14004
                10.1111/jcmm.14004
                6349167
                30426662
                d039026e-c78b-46da-b46c-d5685217dbdd
                © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 July 2018
                : 03 October 2018
                : 12 October 2018
                Page count
                Figures: 8, Tables: 1, Pages: 16, Words: 9186
                Funding
                Funded by: Kaleyde Pharmaceuticals AG
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jcmm14004
                February 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.5.6 mode:remove_FC converted:28.01.2019

                Molecular medicine
                αvβ3 integrin/rac‐1 pathway,aqp2 expression and localization,diabetic kidney disease,ecm markers and renal fibrosis,glomerular morphology and filtration barrier,inflammation markers,standard renal parameters,upar pathway,uparant (cenupatide),vascular permeability

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