FAR2 is associated with kidney disease in mice and humans
Mesangial matrix expansion is an important process in the initiation of chronic kidney disease, yet the genetic factors driving its development are unknown. Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred st...
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| Veröffentlicht in: | Physiological genomics 2018-08, Vol.50 (8), p.543-552 |
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| creator | Backer, Grant Eddy, Sean Sheehan, Susan M Takemon, Yuka Reznichenko, Anna Savage, Holly S Kretzler, Matthias Korstanje, Ron |
| description | Mesangial matrix expansion is an important process in the initiation of chronic kidney disease, yet the genetic factors driving its development are unknown. Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.2. We demonstrate that knockdown of Far2 in mice delays the progression of mesangial matrix expansion with at least six months (equivalent to ~15 yr in human). Furthermore, we show that increased FAR2 expression in human patients is associated with diabetic nephropathy, lupus nephritis, and IgA nephropathy. Taken together, these results highlight FAR2's role in the development of mesangial matrix expansion and chronic kidney disease. |
| doi_str_mv | 10.1152/physiolgenomics.00118.2017 |
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Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.2. We demonstrate that knockdown of Far2 in mice delays the progression of mesangial matrix expansion with at least six months (equivalent to ~15 yr in human). Furthermore, we show that increased FAR2 expression in human patients is associated with diabetic nephropathy, lupus nephritis, and IgA nephropathy. Taken together, these results highlight FAR2's role in the development of mesangial matrix expansion and chronic kidney disease.</description><identifier>ISSN: 1094-8341</identifier><identifier>EISSN: 1531-2267</identifier><identifier>DOI: 10.1152/physiolgenomics.00118.2017</identifier><identifier>PMID: 29652635</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Adult ; Aged ; Aldehyde Oxidoreductases - genetics ; Aldehyde Oxidoreductases - metabolism ; Animals ; Diabetes mellitus ; Diabetic Nephropathies - genetics ; Diabetic Nephropathies - metabolism ; Female ; Genetic factors ; Glomerular Mesangium - metabolism ; Glomerular Mesangium - pathology ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; IgA nephropathy ; Immunoglobulin A ; Inbreeding ; Kidney diseases ; Kidneys ; Lupus nephritis ; Male ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Nephritis ; Nkx3.2 protein ; Platelet-activating factor ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Young Adult</subject><ispartof>Physiological genomics, 2018-08, Vol.50 (8), p.543-552</ispartof><rights>Copyright American Physiological Society Aug 2018</rights><rights>Copyright © 2018 the American Physiological Society 2018 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-6f34e6c6a7a7522d213bc84057a09b5f05c962adbc475fbe65cd094f52bdcd0d3</citedby><cites>FETCH-LOGICAL-c384t-6f34e6c6a7a7522d213bc84057a09b5f05c962adbc475fbe65cd094f52bdcd0d3</cites><orcidid>0000-0002-2808-1610</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3039,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29652635$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Backer, Grant</creatorcontrib><creatorcontrib>Eddy, Sean</creatorcontrib><creatorcontrib>Sheehan, Susan M</creatorcontrib><creatorcontrib>Takemon, Yuka</creatorcontrib><creatorcontrib>Reznichenko, Anna</creatorcontrib><creatorcontrib>Savage, Holly S</creatorcontrib><creatorcontrib>Kretzler, Matthias</creatorcontrib><creatorcontrib>Korstanje, Ron</creatorcontrib><title>FAR2 is associated with kidney disease in mice and humans</title><title>Physiological genomics</title><addtitle>Physiol Genomics</addtitle><description>Mesangial matrix expansion is an important process in the initiation of chronic kidney disease, yet the genetic factors driving its development are unknown. Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.2. We demonstrate that knockdown of Far2 in mice delays the progression of mesangial matrix expansion with at least six months (equivalent to ~15 yr in human). Furthermore, we show that increased FAR2 expression in human patients is associated with diabetic nephropathy, lupus nephritis, and IgA nephropathy. Taken together, these results highlight FAR2's role in the development of mesangial matrix expansion and chronic kidney disease.</description><subject>Adult</subject><subject>Aged</subject><subject>Aldehyde Oxidoreductases - genetics</subject><subject>Aldehyde Oxidoreductases - metabolism</subject><subject>Animals</subject><subject>Diabetes mellitus</subject><subject>Diabetic Nephropathies - genetics</subject><subject>Diabetic Nephropathies - metabolism</subject><subject>Female</subject><subject>Genetic factors</subject><subject>Glomerular Mesangium - metabolism</subject><subject>Glomerular Mesangium - pathology</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>IgA nephropathy</subject><subject>Immunoglobulin A</subject><subject>Inbreeding</subject><subject>Kidney diseases</subject><subject>Kidneys</subject><subject>Lupus nephritis</subject><subject>Male</subject><subject>Mice, Inbred C3H</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Middle Aged</subject><subject>Nephritis</subject><subject>Nkx3.2 protein</subject><subject>Platelet-activating factor</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Young Adult</subject><issn>1094-8341</issn><issn>1531-2267</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkV1P5CAUholxs37tXzBEb7zpLBwKtF6YGOPHJiabbPSaUKAO2sJYWs38exlnNK5XnITnvJzDg9ARJTNKOfxezJfJx-7Bhdh7k2aEUFrNgFC5hXYpZ7QAEHI716Qui4qVdAftpfSYuVJW_CfagVpwEIzvovrq_B9gn7BOKRqvR2fxqx_n-Mnb4JbY-uR0ctgHnN9yWAeL51OvQzpAP1rdJfdrc-6j-6vLu4ub4vbv9Z-L89vCsKocC9Gy0gkjtNSSA1igrDFVSbjUpG54S7ipBWjbmFLytnGCG5vHbjk0NleW7aOzde5ianpnjQvjoDu1GHyvh6WK2qv_b4Kfq4f4ogRltWAyB5xsAob4PLk0qt4n47pOBxenpIBA_jMhyxV6_A19jNMQ8noKKIgauASWqdM1ZYaY0uDaz2EoUStD6psh9W5IrQzl5sOv63y2fihhb4-LkdY</recordid><startdate>20180801</startdate><enddate>20180801</enddate><creator>Backer, Grant</creator><creator>Eddy, Sean</creator><creator>Sheehan, Susan M</creator><creator>Takemon, Yuka</creator><creator>Reznichenko, Anna</creator><creator>Savage, Holly S</creator><creator>Kretzler, Matthias</creator><creator>Korstanje, Ron</creator><general>American Physiological Society</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>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2808-1610</orcidid></search><sort><creationdate>20180801</creationdate><title>FAR2 is associated with kidney disease in mice and humans</title><author>Backer, Grant ; 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Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.2. We demonstrate that knockdown of Far2 in mice delays the progression of mesangial matrix expansion with at least six months (equivalent to ~15 yr in human). Furthermore, we show that increased FAR2 expression in human patients is associated with diabetic nephropathy, lupus nephritis, and IgA nephropathy. 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| subjects | Adult Aged Aldehyde Oxidoreductases - genetics Aldehyde Oxidoreductases - metabolism Animals Diabetes mellitus Diabetic Nephropathies - genetics Diabetic Nephropathies - metabolism Female Genetic factors Glomerular Mesangium - metabolism Glomerular Mesangium - pathology Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans IgA nephropathy Immunoglobulin A Inbreeding Kidney diseases Kidneys Lupus nephritis Male Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Middle Aged Nephritis Nkx3.2 protein Platelet-activating factor Transcription Factors - genetics Transcription Factors - metabolism Young Adult |
| title | FAR2 is associated with kidney disease in mice and humans |
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