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

Salim S. Hayek; Kwi Hye Koh; Morgan E. Grams; Changli Wei; Yi An Ko; Jing Li; Beata Samelko; Hyun Lee; Ranadheer R. Dande; Ha Won Lee; Eunsil Hahm; Vasil Peev; Melissa Tracy; Nicholas J. Tardi; Vineet Gupta; Mehmet M. Altintas; Garrett Garborcauskas; Nikolina Stojanovic; Cheryl A. Winkler; Michael S. Lipkowitz; Adrienne Tin; Lesley A. Inker; Andrew S. Levey; Martin Zeier; Barry I. Freedman; Jeffrey B. Kopp; Karl Skorecki; Josef Coresh; Arshed A. Quyyumi; Sanja Sever; Jochen Reiser

doi:10.1038/nm.4362

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

Salim S. Hayek, Kwi Hye Koh, Morgan E. Grams, Changli Wei, Yi An Ko, Jing Li, Beata Samelko, Hyun Lee, Ranadheer R. Dande, Ha Won Lee, Eunsil Hahm, Vasil Peev, Melissa Tracy, Nicholas J. Tardi, Vineet Gupta, Mehmet M. Altintas, Garrett Garborcauskas, Nikolina Stojanovic, Cheryl A. Winkler, Michael S. LipkowitzAdrienne Tin, Lesley A. Inker, Andrew S. Levey, Martin Zeier, Barry I. Freedman, Jeffrey B. Kopp, Karl Skorecki, Josef Coresh, Arshed A. Quyyumi, Sanja Sever, Jochen Reiser

Research output: Contribution to journal › Article › peer-review

168 Scopus citations

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 v β 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 v β 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 v β 3 integrin activation is a mechanism for CKD.

Original language	English
Pages (from-to)	945-956
Number of pages	12
Journal	Nature Medicine
Volume	23
Issue number	8
DOIs	https://doi.org/10.1038/nm.4362
State	Published - 1 Aug 2017
Externally published	Yes

Bibliographical note

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© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

Funding

S.S.H., K.H.K. and C.W. designed and performed experiments, and wrote the paper; M.E.G. and Y.-A.K. contributed to data analysis; J.L., B.S., H.L., R.R.D., H.W.L., E.H., V.P., M.T., N.J.T., G.G. and N.S. contributed to experiments; K.S. participated in formulating aspects of study design relating to suPAR–APOL1 interaction and developing novel enabling reagents, and collaborated in the writing of the manuscript; V.G., M.M.A., C.A.W., M.S.L., A.T., L.A.I., A.S.L., M.Z., B.I.F., J.B.K. and J.C. contributed to the interpretation of data and manuscript revision; A.A.Q. established the Emory Cardiovascular Biobank that contributed all clinical samples and assisted in manuscript preparation; J.R. and S.S. designed and supervised the study, and wrote the paper. J.R. is supported by grants 5R01DK101350-03 (NIDDK) and 1R01DK106051 (NIDDK). A.A.Q. is supported by grants 5P01HL101398-02, 1P20HL113451-01, 1R56HL126558-01, 1RF1AG051633-01, R01 NS064162-01, R01 HL89650-01, HL095479-01, 1U10HL110302-01, 1DP3DK094346-01, 2P01HL086773-06A1 (NIH). M.E.G., J.C., A.S.L., L.A.I. and A.T. are supported by grants R01DK108803 (NIH) and U01DK085689 (NIDDK). J.C., A.S.L. and L.A.I. are supported by grant R01DK087961 (NIH). E.H. was supported by grant 1RO1 DK106051. Funding for the collection and management of samples was received from the Robert W. Woodruff Health Sciences Center Fund (Atlanta, GA), Emory Heart and Vascular Center (Atlanta, GA), Katz Family Foundation Preventive Cardiology Grant (Atlanta, GA), and National Institutes of Health (NIH) Grants UL1 RR025008 from the Clinical and Translational Science Award program and the Intramural Research Programs of NCI and NIDDK, NIH. This project has also been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Funders	Funder number
Katz Family Foundation
Robert W. Woodruff Health Sciences Center Fund
National Institutes of Health	UL1 RR025008
National Cancer Institute	HHSN26120080001E, ZIABC010022
National Institute of Diabetes and Digestive and Kidney Diseases	U01DK085689, R01DK108803, 1U10HL110302-01, R01DK087961, 1RF1AG051633-01, 1RO1 DK106051, 1P20HL113451-01, R01 NS064162-01, 1R56HL126558-01, R01 HL89650-01, 2P01HL086773-06A1, 5P01HL101398-02, 1DP3DK094346-01, HL095479-01

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Hayek, S. S., Koh, K. H., Grams, M. E., Wei, C., Ko, Y. A., Li, J., Samelko, B., Lee, H., Dande, R. R., Lee, H. W., Hahm, E., Peev, V., Tracy, M., Tardi, N. J., Gupta, V., Altintas, M. M., Garborcauskas, G., Stojanovic, N., Winkler, C. A., ... Reiser, J. (2017). A tripartite complex of suPAR, APOL1 risk variants and α v β 3 integrin on podocytes mediates chronic kidney disease. Nature Medicine, 23(8), 945-956. https://doi.org/10.1038/nm.4362

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title = "A tripartite complex of suPAR, APOL1 risk variants and α v β 3 integrin on podocytes mediates chronic kidney disease",

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 v β 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 v β 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 v β 3 integrin activation is a mechanism for CKD.",

author = "Hayek, {Salim S.} and Koh, {Kwi Hye} and Grams, {Morgan E.} and Changli Wei and Ko, {Yi An} and Jing Li and Beata Samelko and Hyun Lee and Dande, {Ranadheer R.} and Lee, {Ha Won} and Eunsil Hahm and Vasil Peev and Melissa Tracy and Tardi, {Nicholas J.} and Vineet Gupta and Altintas, {Mehmet M.} and Garrett Garborcauskas and Nikolina Stojanovic and Winkler, {Cheryl A.} and Lipkowitz, {Michael S.} and Adrienne Tin and Inker, {Lesley A.} and Levey, {Andrew S.} and Martin Zeier and Freedman, {Barry I.} and Kopp, {Jeffrey B.} and Karl Skorecki and Josef Coresh and Quyyumi, {Arshed A.} and Sanja Sever and Jochen Reiser",

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Hayek, SS, Koh, KH, Grams, ME, Wei, C, Ko, YA, Li, J, Samelko, B, Lee, H, Dande, RR, Lee, HW, Hahm, E, Peev, V, Tracy, M, Tardi, NJ, Gupta, V, Altintas, MM, Garborcauskas, G, Stojanovic, N, Winkler, CA, Lipkowitz, MS, Tin, A, Inker, LA, Levey, AS, Zeier, M, Freedman, BI, Kopp, JB, Skorecki, K, Coresh, J, Quyyumi, AA, Sever, S & Reiser, J 2017, 'A tripartite complex of suPAR, APOL1 risk variants and α v β 3 integrin on podocytes mediates chronic kidney disease', Nature Medicine, vol. 23, no. 8, pp. 945-956. https://doi.org/10.1038/nm.4362

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AU - Hayek, Salim S.

AU - Koh, Kwi Hye

AU - Grams, Morgan E.

AU - Wei, Changli

AU - Ko, Yi An

AU - Li, Jing

AU - Samelko, Beata

AU - Lee, Hyun

AU - Dande, Ranadheer R.

AU - Lee, Ha Won

AU - Hahm, Eunsil

AU - Peev, Vasil

AU - Tracy, Melissa

AU - Tardi, Nicholas J.

AU - Gupta, Vineet

AU - Altintas, Mehmet M.

AU - Garborcauskas, Garrett

AU - Stojanovic, Nikolina

AU - Winkler, Cheryl A.

AU - Lipkowitz, Michael S.

AU - Tin, Adrienne

AU - Inker, Lesley A.

AU - Levey, Andrew S.

AU - Zeier, Martin

AU - Freedman, Barry I.

AU - Kopp, Jeffrey B.

AU - Skorecki, Karl

AU - Coresh, Josef

AU - Quyyumi, Arshed A.

AU - Sever, Sanja

AU - Reiser, Jochen

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

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