Targeting Sirtuin-1 prolongs murine renal allograft survival and function
Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ T-re...
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| Veröffentlicht in: | Kidney international 2016-05, Vol.89 (5), p.1016-1026 |
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| creator | Levine, Matthew H. Wang, Zhonglin Xiao, Haiyan Jiao, Jing Wang, Liqing Bhatti, Tricia R. Hancock, Wayne W. Beier, Ulf H. |
| description | Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1–specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell–mediated rejection. However, effects on non–T cells that could adversely affect allograft survival and function merit consideration. |
| doi_str_mv | 10.1016/j.kint.2015.12.051 |
| format | Article |
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Foxp3+ T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1–specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell–mediated rejection. However, effects on non–T cells that could adversely affect allograft survival and function merit consideration.</description><identifier>ISSN: 0085-2538</identifier><identifier>EISSN: 1523-1755</identifier><identifier>DOI: 10.1016/j.kint.2015.12.051</identifier><identifier>PMID: 27083279</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>acute rejection ; Allografts ; Animals ; Carbazoles - pharmacology ; chronic allograft nephropathy ; Female ; Graft Rejection - enzymology ; Graft Rejection - immunology ; Graft Rejection - physiopathology ; Graft Rejection - prevention & control ; Graft Survival - drug effects ; Histone Deacetylase Inhibitors - pharmacology ; Immunosuppressive Agents - pharmacology ; Kidney - drug effects ; Kidney - enzymology ; Kidney - immunology ; Kidney - physiopathology ; Kidney Transplantation - adverse effects ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Sirtuin 1 - antagonists & inhibitors ; Sirtuin 1 - deficiency ; Sirtuin 1 - genetics ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - enzymology ; T-Lymphocytes, Regulatory - immunology ; Time Factors ; tolerance ; Transplantation Tolerance - drug effects</subject><ispartof>Kidney international, 2016-05, Vol.89 (5), p.1016-1026</ispartof><rights>2016 International Society of Nephrology</rights><rights>Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-4e3c24bae62abca2f6f419444f2c889ac86fbfe2ce8d8caaa853ca145959eac03</citedby><cites>FETCH-LOGICAL-c455t-4e3c24bae62abca2f6f419444f2c889ac86fbfe2ce8d8caaa853ca145959eac03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27083279$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Levine, Matthew H.</creatorcontrib><creatorcontrib>Wang, Zhonglin</creatorcontrib><creatorcontrib>Xiao, Haiyan</creatorcontrib><creatorcontrib>Jiao, Jing</creatorcontrib><creatorcontrib>Wang, Liqing</creatorcontrib><creatorcontrib>Bhatti, Tricia R.</creatorcontrib><creatorcontrib>Hancock, Wayne W.</creatorcontrib><creatorcontrib>Beier, Ulf H.</creatorcontrib><title>Targeting Sirtuin-1 prolongs murine renal allograft survival and function</title><title>Kidney international</title><addtitle>Kidney Int</addtitle><description>Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1–specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell–mediated rejection. However, effects on non–T cells that could adversely affect allograft survival and function merit consideration.</description><subject>acute rejection</subject><subject>Allografts</subject><subject>Animals</subject><subject>Carbazoles - pharmacology</subject><subject>chronic allograft nephropathy</subject><subject>Female</subject><subject>Graft Rejection - enzymology</subject><subject>Graft Rejection - immunology</subject><subject>Graft Rejection - physiopathology</subject><subject>Graft Rejection - prevention & control</subject><subject>Graft Survival - drug effects</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Kidney - drug effects</subject><subject>Kidney - enzymology</subject><subject>Kidney - immunology</subject><subject>Kidney - physiopathology</subject><subject>Kidney Transplantation - adverse effects</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C3H</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Phenotype</subject><subject>Sirtuin 1 - antagonists & inhibitors</subject><subject>Sirtuin 1 - deficiency</subject><subject>Sirtuin 1 - genetics</subject><subject>T-Lymphocytes, Regulatory - drug effects</subject><subject>T-Lymphocytes, Regulatory - enzymology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Time Factors</subject><subject>tolerance</subject><subject>Transplantation Tolerance - drug effects</subject><issn>0085-2538</issn><issn>1523-1755</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1rGzEQFSWhdj7-QA5lj7nsVp-2FkqhhLYJBHJoehZj7WgjZy25ktaQf981Tkx7yWmYmffeDO8RcsVowyhbfF43zz6UhlOmGsYbqtgHMmeKi5otlTohc0q1qrkSekbOcl7TqW8F_UhmfEm14Mt2Tu4eIfVYfOirXz6V0YeaVdsUhxj6XG3G5ANWCQMMFQxD7BO4UuUx7fxuPwpd5cZgi4_hgpw6GDJevtZz8vvH98eb2_r-4efdzbf72kqlSi1RWC5XgAsOKwvcLZxkrZTScat1C1Yv3Moht6g7bQFAK2GBSdWqFsFScU6-HnS342qDncVQEgxmm_wG0ouJ4M3_m-CfTB93RmohmRSTwPWrQIp_RszFbHy2OAwQMI7ZsKVmSvK21ROUH6A2xZwTuuMZRs0-A7M2-wzMPgPDuJkymEif_n3wSHkzfQJ8OQBwsmnnMZlsPQaLnU9oi-mif0__L844m1E</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Levine, Matthew H.</creator><creator>Wang, Zhonglin</creator><creator>Xiao, Haiyan</creator><creator>Jiao, Jing</creator><creator>Wang, Liqing</creator><creator>Bhatti, Tricia R.</creator><creator>Hancock, Wayne W.</creator><creator>Beier, Ulf H.</creator><general>Elsevier Inc</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160501</creationdate><title>Targeting Sirtuin-1 prolongs murine renal allograft survival and function</title><author>Levine, Matthew H. ; Wang, Zhonglin ; Xiao, Haiyan ; Jiao, Jing ; Wang, Liqing ; Bhatti, Tricia R. ; Hancock, Wayne W. ; Beier, Ulf H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-4e3c24bae62abca2f6f419444f2c889ac86fbfe2ce8d8caaa853ca145959eac03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>acute rejection</topic><topic>Allografts</topic><topic>Animals</topic><topic>Carbazoles - pharmacology</topic><topic>chronic allograft nephropathy</topic><topic>Female</topic><topic>Graft Rejection - enzymology</topic><topic>Graft Rejection - immunology</topic><topic>Graft Rejection - physiopathology</topic><topic>Graft Rejection - prevention & control</topic><topic>Graft Survival - drug effects</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Immunosuppressive Agents - pharmacology</topic><topic>Kidney - drug effects</topic><topic>Kidney - enzymology</topic><topic>Kidney - immunology</topic><topic>Kidney - physiopathology</topic><topic>Kidney Transplantation - adverse effects</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred C3H</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Phenotype</topic><topic>Sirtuin 1 - antagonists & inhibitors</topic><topic>Sirtuin 1 - deficiency</topic><topic>Sirtuin 1 - genetics</topic><topic>T-Lymphocytes, Regulatory - drug effects</topic><topic>T-Lymphocytes, Regulatory - enzymology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Time Factors</topic><topic>tolerance</topic><topic>Transplantation Tolerance - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Levine, Matthew H.</creatorcontrib><creatorcontrib>Wang, Zhonglin</creatorcontrib><creatorcontrib>Xiao, Haiyan</creatorcontrib><creatorcontrib>Jiao, Jing</creatorcontrib><creatorcontrib>Wang, Liqing</creatorcontrib><creatorcontrib>Bhatti, Tricia R.</creatorcontrib><creatorcontrib>Hancock, Wayne W.</creatorcontrib><creatorcontrib>Beier, Ulf H.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Kidney international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Levine, Matthew H.</au><au>Wang, Zhonglin</au><au>Xiao, Haiyan</au><au>Jiao, Jing</au><au>Wang, Liqing</au><au>Bhatti, Tricia R.</au><au>Hancock, Wayne W.</au><au>Beier, Ulf H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting Sirtuin-1 prolongs murine renal allograft survival and function</atitle><jtitle>Kidney international</jtitle><addtitle>Kidney Int</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>89</volume><issue>5</issue><spage>1016</spage><epage>1026</epage><pages>1016-1026</pages><issn>0085-2538</issn><eissn>1523-1755</eissn><abstract>Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1–specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell–mediated rejection. However, effects on non–T cells that could adversely affect allograft survival and function merit consideration.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27083279</pmid><doi>10.1016/j.kint.2015.12.051</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | acute rejection Allografts Animals Carbazoles - pharmacology chronic allograft nephropathy Female Graft Rejection - enzymology Graft Rejection - immunology Graft Rejection - physiopathology Graft Rejection - prevention & control Graft Survival - drug effects Histone Deacetylase Inhibitors - pharmacology Immunosuppressive Agents - pharmacology Kidney - drug effects Kidney - enzymology Kidney - immunology Kidney - physiopathology Kidney Transplantation - adverse effects Mice, Inbred BALB C Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Phenotype Sirtuin 1 - antagonists & inhibitors Sirtuin 1 - deficiency Sirtuin 1 - genetics T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - enzymology T-Lymphocytes, Regulatory - immunology Time Factors tolerance Transplantation Tolerance - drug effects |
| title | Targeting Sirtuin-1 prolongs murine renal allograft survival and function |
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