Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton
FKBP12 was identified as a binding protein of tacrolimus (Tac). Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac i...
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| Veröffentlicht in: | The FASEB journal 2021-11, Vol.35 (11), p.e21983-n/a |
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| creator | Yasuda, Hidenori Fukusumi, Yoshiyasu Ivanov, Veniamin Zhang, Ying Kawachi, Hiroshi |
| description | FKBP12 was identified as a binding protein of tacrolimus (Tac). Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac is not well understood yet. It is also known that FKBP12 functions independently of Tac. However, the localization and the physiological function of FKBP12 are not well elucidated. In this study, we observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 in cultured podocytes was expressed along the actin cytoskeleton and associated with filamentous actin (F‐actin). FKBP12 interacted with the actin‐associated proteins 14‐3‐3 and synaptopodin. RNA silencing for FKBP12 reduced 14‐3‐3 expression, F‐actin staining, and process formation in cultured podocytes. FKBP12 expression was decreased in the nephrotic model caused by adriamycin (ADR) and the cultured podocyte treated with ADR. The process formation was deteriorated in the podocytes treated with ADR. Tac treatment ameliorated these decreases. Tac treatment to the normal cells increased the expression of FKBP12 at F‐actin in processes and enhanced process formation. Tac enhanced the interaction of FKBP12 with synaptopodin. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of processes, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton. |
| doi_str_mv | 10.1096/fj.202101052R |
| format | Article |
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Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac is not well understood yet. It is also known that FKBP12 functions independently of Tac. However, the localization and the physiological function of FKBP12 are not well elucidated. In this study, we observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 in cultured podocytes was expressed along the actin cytoskeleton and associated with filamentous actin (F‐actin). FKBP12 interacted with the actin‐associated proteins 14‐3‐3 and synaptopodin. RNA silencing for FKBP12 reduced 14‐3‐3 expression, F‐actin staining, and process formation in cultured podocytes. FKBP12 expression was decreased in the nephrotic model caused by adriamycin (ADR) and the cultured podocyte treated with ADR. The process formation was deteriorated in the podocytes treated with ADR. Tac treatment ameliorated these decreases. Tac treatment to the normal cells increased the expression of FKBP12 at F‐actin in processes and enhanced process formation. Tac enhanced the interaction of FKBP12 with synaptopodin. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of processes, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.202101052R</identifier><language>eng</language><subject>actin cytoskeleton ; calcineurin inhibitor ; glomerular epithelial cell ; immunofilin ; nephropathy ; proteinuria</subject><ispartof>The FASEB journal, 2021-11, Vol.35 (11), p.e21983-n/a</ispartof><rights>2021 The Authors. published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4203-ded24cd4e0b43b703e3dac650ecabb1c9d10ca12a19bb88307d80c0a3ecc83aa3</citedby><cites>FETCH-LOGICAL-c4203-ded24cd4e0b43b703e3dac650ecabb1c9d10ca12a19bb88307d80c0a3ecc83aa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.202101052R$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.202101052R$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids></links><search><creatorcontrib>Yasuda, Hidenori</creatorcontrib><creatorcontrib>Fukusumi, Yoshiyasu</creatorcontrib><creatorcontrib>Ivanov, Veniamin</creatorcontrib><creatorcontrib>Zhang, Ying</creatorcontrib><creatorcontrib>Kawachi, Hiroshi</creatorcontrib><title>Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton</title><title>The FASEB journal</title><description>FKBP12 was identified as a binding protein of tacrolimus (Tac). Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac is not well understood yet. It is also known that FKBP12 functions independently of Tac. However, the localization and the physiological function of FKBP12 are not well elucidated. In this study, we observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 in cultured podocytes was expressed along the actin cytoskeleton and associated with filamentous actin (F‐actin). FKBP12 interacted with the actin‐associated proteins 14‐3‐3 and synaptopodin. RNA silencing for FKBP12 reduced 14‐3‐3 expression, F‐actin staining, and process formation in cultured podocytes. FKBP12 expression was decreased in the nephrotic model caused by adriamycin (ADR) and the cultured podocyte treated with ADR. The process formation was deteriorated in the podocytes treated with ADR. Tac treatment ameliorated these decreases. Tac treatment to the normal cells increased the expression of FKBP12 at F‐actin in processes and enhanced process formation. Tac enhanced the interaction of FKBP12 with synaptopodin. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of processes, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton.</description><subject>actin cytoskeleton</subject><subject>calcineurin inhibitor</subject><subject>glomerular epithelial cell</subject><subject>immunofilin</subject><subject>nephropathy</subject><subject>proteinuria</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp9kMFLwzAUxoMoOKdH7znOQ-dL0nbp0Q2r4kDReS5p-irpumYmLdL_3owJ3jw9vsePj48fIdcM5gyy9LZu5hw4AwYJfzshE5YIiFKZwimZgMx4lKZCnpML7xuAQLF0QrYbpZ1tzW7wVO2wNdapHj3d28rqsUdqumZwIy1H6tD31pnuk-bPCaS0NF11SHtnezQdZZzO8uflK-M3VPVU6T48Q4f1W2yxt90lOatV6_Hq907JR36_WT1G65eHp9XdOtIxBxFVWPFYVzFCGYtyAQJFpXSaAGpVlkxnFQOtGFcsK0spBSwqCRqUQK2lUEpMyezYG5Z9DWF1sTNeY9uqDu3gC55IEcdMikVAoyMaJHjvsC72zuyUGwsGxUFqUTfFn9TAx0f-27Q4_g8X-fuSc5ZJIX4AhWx6WA</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>Yasuda, Hidenori</creator><creator>Fukusumi, Yoshiyasu</creator><creator>Ivanov, Veniamin</creator><creator>Zhang, Ying</creator><creator>Kawachi, Hiroshi</creator><scope>24P</scope><scope>WIN</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202111</creationdate><title>Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton</title><author>Yasuda, Hidenori ; Fukusumi, Yoshiyasu ; Ivanov, Veniamin ; Zhang, Ying ; Kawachi, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4203-ded24cd4e0b43b703e3dac650ecabb1c9d10ca12a19bb88307d80c0a3ecc83aa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>actin cytoskeleton</topic><topic>calcineurin inhibitor</topic><topic>glomerular epithelial cell</topic><topic>immunofilin</topic><topic>nephropathy</topic><topic>proteinuria</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yasuda, Hidenori</creatorcontrib><creatorcontrib>Fukusumi, Yoshiyasu</creatorcontrib><creatorcontrib>Ivanov, Veniamin</creatorcontrib><creatorcontrib>Zhang, Ying</creatorcontrib><creatorcontrib>Kawachi, Hiroshi</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yasuda, Hidenori</au><au>Fukusumi, Yoshiyasu</au><au>Ivanov, Veniamin</au><au>Zhang, Ying</au><au>Kawachi, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton</atitle><jtitle>The FASEB journal</jtitle><date>2021-11</date><risdate>2021</risdate><volume>35</volume><issue>11</issue><spage>e21983</spage><epage>n/a</epage><pages>e21983-n/a</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>FKBP12 was identified as a binding protein of tacrolimus (Tac). Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac is not well understood yet. It is also known that FKBP12 functions independently of Tac. However, the localization and the physiological function of FKBP12 are not well elucidated. In this study, we observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 in cultured podocytes was expressed along the actin cytoskeleton and associated with filamentous actin (F‐actin). FKBP12 interacted with the actin‐associated proteins 14‐3‐3 and synaptopodin. RNA silencing for FKBP12 reduced 14‐3‐3 expression, F‐actin staining, and process formation in cultured podocytes. FKBP12 expression was decreased in the nephrotic model caused by adriamycin (ADR) and the cultured podocyte treated with ADR. The process formation was deteriorated in the podocytes treated with ADR. Tac treatment ameliorated these decreases. Tac treatment to the normal cells increased the expression of FKBP12 at F‐actin in processes and enhanced process formation. Tac enhanced the interaction of FKBP12 with synaptopodin. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of processes, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton.</abstract><doi>10.1096/fj.202101052R</doi><tpages>19</tpages><oa>free_for_read</oa></addata></record> |
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| source | Wiley Online Library Journals Frontfile Complete; Alma/SFX Local Collection |
| subjects | actin cytoskeleton calcineurin inhibitor glomerular epithelial cell immunofilin nephropathy proteinuria |
| title | Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton |
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