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      A tripartite complex of suPAR, APOL1 risk variants and α vβ 3 integrin on podocytes mediates chronic kidney disease

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          Abstract

          Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and α vβ 3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments α vβ 3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on α vβ 3 integrin activation is a mechanism for CKD.

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          APOL1 risk variants, race, and progression of chronic kidney disease.

          Afshin Parsa, W.H. Linda Kao, Dawei Xie … (2013)
          Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
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            Modification of kidney barrier function by the urokinase receptor.

            Jochen Reiser, Mehmet Altintas, Moise Bendayan … (2007)
            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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              Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

              Pazit Beckerman, Jing Bi-Karchin, Ae Seo Deok Park … (2017)
              Risk variants of APOL1 associated with human chronic kidney disease have been identified, but causality has been unclear. Transgenic expression in mice now shows that such alleles can indeed cause renal disease.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Journal ID (iso-abbrev): Nat. Med.
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 15 June 2018
                Publication date (Electronic): 26 June 2017
                Publication date (Print): August 2017
                Publication date PMC-release: 26 June 2018
                Volume: 23
                Issue: 8
                Pages: 945-953
                Affiliations
                [1 ]Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA
                [2 ]Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
                [3 ]Welch Center for Prevention and Johns Hopkins Bloomberg School of Public Health, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA
                [4 ]Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, USA
                [5 ]Center for Biomolecular Science and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA
                [6 ]Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA
                [7 ]Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA
                [8 ]Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC, USA
                [9 ]Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA
                [10 ]Division of Nephrology, Ruprecht Karls University, Heidelberg, Germany
                [11 ]Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
                [12 ]Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
                [13 ]Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Rambam Health Care Campus, Haifa, Israel
                Author notes
                Correspondence should be addressed to S.S. ( ssever@ 123456mgh.harvard.edu ) or J.R. ( jochen_reiser@ 123456rush.edu )
                [14]

                These authors contributed equally to this work.

                Salim S Hayek http://orcid.org/0000-0003-0180-349X

                Eunsil Hahm http://orcid.org/0000-0002-0343-7473

                Vineet Gupta http://orcid.org/0000-0001-6987-2550

                Cheryl A Winkler http://orcid.org/0000-0001-5552-0917

                Article
                Accession ID: PMC6019326 Pmcid ID: PMC6019326 Pmc-uid ID: 6019326 Manuscript ID: nihpa974422
                DOI: 10.1038/nm.4362
                PMC ID: 6019326
                PubMed ID: 28650456
                SO-VID: 35cb8ab3-fade-415b-8e0d-b3a7ac151e97
                License:

                Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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