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

Bloomberg School of Public Health

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

95 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 (US)
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 - Aug 1 2017

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm.4362

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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

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

@article{aea917e435764c3284ffca12825e74a9,

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",

year = "2017",

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doi = "10.1038/nm.4362",

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T1 - A tripartite complex of suPAR, APOL1 risk variants and α v β 3 integrin on podocytes mediates chronic kidney disease

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

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

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JO - Nature medicine

JF - Nature medicine

IS - 8

ER -

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

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