Variant APOL1 protein in plasma associates with larger particles in humans and mouse models of kidney injury

Genetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney c...

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Veröffentlicht in:PloS one 2022-10, Vol.17 (10), p.e0276649-e0276649
Hauptverfasser: Andrews, Michael, Yoshida, Teruhiko, Henderson, Clark M, Pflaum, Hannah, McGregor, Ayako, Lieberman, Joshua A, de Boer, Ian H, Vaisar, Tomas, Himmelfarb, Jonathan, Kestenbaum, Bryan, Chung, Joon-Yong, Hewitt, Stephen M, Santo, Briana A, Ginley, Brandon, Sarder, Pinaki, Rosenberg, Avi Z, Murakami, Taichi, Kopp, Jeffrey B, Kuklenyik, Zsuzsanna, Hoofnagle, Andrew N
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container_issue 10
container_start_page e0276649
container_title PloS one
container_volume 17
creator Andrews, Michael
Yoshida, Teruhiko
Henderson, Clark M
Pflaum, Hannah
McGregor, Ayako
Lieberman, Joshua A
de Boer, Ian H
Vaisar, Tomas
Himmelfarb, Jonathan
Kestenbaum, Bryan
Chung, Joon-Yong
Hewitt, Stephen M
Santo, Briana A
Ginley, Brandon
Sarder, Pinaki
Rosenberg, Avi Z
Murakami, Taichi
Kopp, Jeffrey B
Kuklenyik, Zsuzsanna
Hoofnagle, Andrew N
description Genetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury. Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology. In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1. These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.
doi_str_mv 10.1371/journal.pone.0276649
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The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury. Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology. In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1. These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0276649</identifier><identifier>PMID: 36279295</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Albumin ; Albumins ; Analysis ; Animal models ; Animals ; Apolipoprotein L1 - genetics ; Apolipoprotein L1 - metabolism ; Apolipoproteins ; Apolipoproteins - genetics ; Biology and Life Sciences ; Chromatography ; Chronic kidney failure ; Creatinine ; Damage ; Disease ; Disease Models, Animal ; Engineering and Technology ; Evaluation ; Fibroblasts ; Fractionation ; Genetic diversity ; Genetic engineering ; Genetic variance ; Genotype &amp; phenotype ; Genotypes ; Growth factors ; Health aspects ; Health risks ; Humans ; Injuries ; Kidney - pathology ; Kidney diseases ; Kidney transplantation ; Kidneys ; Kinases ; Laboratory animals ; Liquid chromatography ; Mass spectrometry ; Mass spectroscopy ; Measurement ; Medicine and Health Sciences ; Methods ; Mice ; Mice, Transgenic ; Peptides ; Plasma ; Polymorphism ; Prevention ; Proteins ; Renal Insufficiency, Chronic - genetics ; Renal Insufficiency, Chronic - pathology ; Research and Analysis Methods ; Risk ; Risk factors ; Transgenic animals ; Transgenic mice ; Transplantation ; Urine</subject><ispartof>PloS one, 2022-10, Vol.17 (10), p.e0276649-e0276649</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 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The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury. Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology. In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1. These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.</description><subject>Albumin</subject><subject>Albumins</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apolipoprotein L1 - genetics</subject><subject>Apolipoprotein L1 - metabolism</subject><subject>Apolipoproteins</subject><subject>Apolipoproteins - genetics</subject><subject>Biology and Life Sciences</subject><subject>Chromatography</subject><subject>Chronic kidney failure</subject><subject>Creatinine</subject><subject>Damage</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Engineering and Technology</subject><subject>Evaluation</subject><subject>Fibroblasts</subject><subject>Fractionation</subject><subject>Genetic diversity</subject><subject>Genetic engineering</subject><subject>Genetic variance</subject><subject>Genotype &amp; phenotype</subject><subject>Genotypes</subject><subject>Growth factors</subject><subject>Health aspects</subject><subject>Health risks</subject><subject>Humans</subject><subject>Injuries</subject><subject>Kidney - pathology</subject><subject>Kidney diseases</subject><subject>Kidney transplantation</subject><subject>Kidneys</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Liquid chromatography</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Measurement</subject><subject>Medicine and Health Sciences</subject><subject>Methods</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Peptides</subject><subject>Plasma</subject><subject>Polymorphism</subject><subject>Prevention</subject><subject>Proteins</subject><subject>Renal Insufficiency, Chronic - genetics</subject><subject>Renal Insufficiency, Chronic - pathology</subject><subject>Research and Analysis Methods</subject><subject>Risk</subject><subject>Risk factors</subject><subject>Transgenic animals</subject><subject>Transgenic mice</subject><subject>Transplantation</subject><subject>Urine</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptkl2LEzEUhgdR3HX1H4gOCOJNa74mHzdCWfxYKKwX6m3IJJk2NZOMyYzSf2-6nV1aEUISkue857yHU1UvIVhCzOD7XZxSUH45xGCXADFKiXhUXUKB0YIigB-f3C-qZznvAGgwp_RpdYEpYgKJ5rLyP1RyKoz16uvtGtZDiqN1oS5r8Cr3qlY5R-3UaHP9x43b2qu0sakeVBqd9uW1oNupVyHXKpi6j1O2ZTfW5zp29U9ngt0XaDel_fPqSad8ti_m86r6_unjt-svi_Xt55vr1XqhG96MC4NbawAREBFuEBWcs44R0yEKcDGDCW2RoG2nETdAWwsh6SzVlAltNDcQX1Wvj7qDj1nOjcoSMcRBgxBFhbg5EiaqnRyS61Xay6icvHuIaSNngxIqAyETmLQGESjaFiGOOmgJMAZhddD6MGeb2t4abcOYlD8TPf8Jbis38bcUjYCg4UXg3SyQ4q_J5lH2LmvrvQq2tPOubkgYbGhB3_yD_t_dTG1UMeBCF0tefRCVK4YwZ7xpDtTbE2prlR-3OfppdDHkc5AcQZ1izsl2D94gkIdZvC9CHmZRzrNYwl6d9uUh6H748F8JVtuA</recordid><startdate>20221024</startdate><enddate>20221024</enddate><creator>Andrews, Michael</creator><creator>Yoshida, Teruhiko</creator><creator>Henderson, Clark M</creator><creator>Pflaum, Hannah</creator><creator>McGregor, Ayako</creator><creator>Lieberman, Joshua A</creator><creator>de Boer, Ian H</creator><creator>Vaisar, Tomas</creator><creator>Himmelfarb, Jonathan</creator><creator>Kestenbaum, Bryan</creator><creator>Chung, Joon-Yong</creator><creator>Hewitt, Stephen M</creator><creator>Santo, Briana A</creator><creator>Ginley, Brandon</creator><creator>Sarder, Pinaki</creator><creator>Rosenberg, Avi Z</creator><creator>Murakami, Taichi</creator><creator>Kopp, Jeffrey B</creator><creator>Kuklenyik, Zsuzsanna</creator><creator>Hoofnagle, Andrew N</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-1958-909X</orcidid><orcidid>https://orcid.org/0000-0001-9801-7705</orcidid><orcidid>https://orcid.org/0000-0002-2049-7347</orcidid><orcidid>https://orcid.org/0000-0002-6449-0243</orcidid><orcidid>https://orcid.org/0000-0002-7406-6606</orcidid></search><sort><creationdate>20221024</creationdate><title>Variant APOL1 protein in plasma associates with larger particles in humans and mouse models of kidney injury</title><author>Andrews, Michael ; Yoshida, Teruhiko ; Henderson, Clark M ; Pflaum, Hannah ; McGregor, Ayako ; Lieberman, Joshua A ; de Boer, Ian H ; Vaisar, Tomas ; Himmelfarb, Jonathan ; Kestenbaum, Bryan ; Chung, Joon-Yong ; Hewitt, Stephen M ; Santo, Briana A ; Ginley, Brandon ; Sarder, Pinaki ; Rosenberg, Avi Z ; Murakami, Taichi ; Kopp, Jeffrey B ; Kuklenyik, Zsuzsanna ; Hoofnagle, Andrew N</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c585t-d3bed0491248d269887f74df2603203346b296bfc28d0cee114fe6c679cdc8d13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Albumin</topic><topic>Albumins</topic><topic>Analysis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Apolipoprotein L1 - genetics</topic><topic>Apolipoprotein L1 - metabolism</topic><topic>Apolipoproteins</topic><topic>Apolipoproteins - genetics</topic><topic>Biology and Life Sciences</topic><topic>Chromatography</topic><topic>Chronic kidney failure</topic><topic>Creatinine</topic><topic>Damage</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>Engineering and Technology</topic><topic>Evaluation</topic><topic>Fibroblasts</topic><topic>Fractionation</topic><topic>Genetic diversity</topic><topic>Genetic engineering</topic><topic>Genetic variance</topic><topic>Genotype &amp; 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Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health &amp; Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied &amp; Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Andrews, Michael</au><au>Yoshida, Teruhiko</au><au>Henderson, Clark M</au><au>Pflaum, Hannah</au><au>McGregor, Ayako</au><au>Lieberman, Joshua A</au><au>de Boer, Ian H</au><au>Vaisar, Tomas</au><au>Himmelfarb, Jonathan</au><au>Kestenbaum, Bryan</au><au>Chung, Joon-Yong</au><au>Hewitt, Stephen M</au><au>Santo, Briana A</au><au>Ginley, Brandon</au><au>Sarder, Pinaki</au><au>Rosenberg, Avi Z</au><au>Murakami, Taichi</au><au>Kopp, Jeffrey B</au><au>Kuklenyik, Zsuzsanna</au><au>Hoofnagle, Andrew N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Variant APOL1 protein in plasma associates with larger particles in humans and mouse models of kidney injury</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2022-10-24</date><risdate>2022</risdate><volume>17</volume><issue>10</issue><spage>e0276649</spage><epage>e0276649</epage><pages>e0276649-e0276649</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Genetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury. Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology. In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1. These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>36279295</pmid><doi>10.1371/journal.pone.0276649</doi><orcidid>https://orcid.org/0000-0003-1958-909X</orcidid><orcidid>https://orcid.org/0000-0001-9801-7705</orcidid><orcidid>https://orcid.org/0000-0002-2049-7347</orcidid><orcidid>https://orcid.org/0000-0002-6449-0243</orcidid><orcidid>https://orcid.org/0000-0002-7406-6606</orcidid><oa>free_for_read</oa></addata></record>
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1932-6203
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source Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry
subjects Albumin
Albumins
Analysis
Animal models
Animals
Apolipoprotein L1 - genetics
Apolipoprotein L1 - metabolism
Apolipoproteins
Apolipoproteins - genetics
Biology and Life Sciences
Chromatography
Chronic kidney failure
Creatinine
Damage
Disease
Disease Models, Animal
Engineering and Technology
Evaluation
Fibroblasts
Fractionation
Genetic diversity
Genetic engineering
Genetic variance
Genotype & phenotype
Genotypes
Growth factors
Health aspects
Health risks
Humans
Injuries
Kidney - pathology
Kidney diseases
Kidney transplantation
Kidneys
Kinases
Laboratory animals
Liquid chromatography
Mass spectrometry
Mass spectroscopy
Measurement
Medicine and Health Sciences
Methods
Mice
Mice, Transgenic
Peptides
Plasma
Polymorphism
Prevention
Proteins
Renal Insufficiency, Chronic - genetics
Renal Insufficiency, Chronic - pathology
Research and Analysis Methods
Risk
Risk factors
Transgenic animals
Transgenic mice
Transplantation
Urine
title Variant APOL1 protein in plasma associates with larger particles in humans and mouse models of kidney injury
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