Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury
Renal ischemia-reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in...
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| Veröffentlicht in: | Nephrology, dialysis, transplantation dialysis, transplantation, 2021-01, Vol.36 (2), p.257-266 |
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| creator | Ding, Meiwen Tolbert, Evelyn Birkenbach, Mark Akhlaghi, Fatemeh Gohh, Reginald Ghonem, Nisanne S |
| description | Renal ischemia-reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in vivo.
Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1-168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18-24 h before ischemia.
Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil.
This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo. |
| doi_str_mv | 10.1093/ndt/gfaa236 |
| format | Article |
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Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1-168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18-24 h before ischemia.
Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil.
This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo.</description><identifier>ISSN: 0931-0509</identifier><identifier>EISSN: 1460-2385</identifier><identifier>DOI: 10.1093/ndt/gfaa236</identifier><identifier>PMID: 33156922</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Acute Kidney Injury - drug therapy ; Acute Kidney Injury - etiology ; Acute Kidney Injury - metabolism ; Acute Kidney Injury - pathology ; Animals ; Antihypertensive Agents - pharmacology ; Biomarkers - metabolism ; Blood Urea Nitrogen ; Caspase 3 - metabolism ; Creatinine - blood ; Disease Models, Animal ; Epoprostenol - analogs & derivatives ; Epoprostenol - pharmacology ; Interleukin-1beta - metabolism ; Kidney Function Tests ; Lipocalin-2 - metabolism ; Male ; ORIGINAL ARTICLES ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury - complications</subject><ispartof>Nephrology, dialysis, transplantation, 2021-01, Vol.36 (2), p.257-266</ispartof><rights>The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.</rights><rights>The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-df23b49c8b202c96c01cd6cf5a8513680a3400d1e8e4389836d054ac52d951083</citedby><cites>FETCH-LOGICAL-c381t-df23b49c8b202c96c01cd6cf5a8513680a3400d1e8e4389836d054ac52d951083</cites><orcidid>0000-0002-4724-0576</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33156922$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ding, Meiwen</creatorcontrib><creatorcontrib>Tolbert, Evelyn</creatorcontrib><creatorcontrib>Birkenbach, Mark</creatorcontrib><creatorcontrib>Akhlaghi, Fatemeh</creatorcontrib><creatorcontrib>Gohh, Reginald</creatorcontrib><creatorcontrib>Ghonem, Nisanne S</creatorcontrib><title>Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury</title><title>Nephrology, dialysis, transplantation</title><addtitle>Nephrol Dial Transplant</addtitle><description>Renal ischemia-reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in vivo.
Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1-168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18-24 h before ischemia.
Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil.
This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo.</description><subject>Acute Kidney Injury - drug therapy</subject><subject>Acute Kidney Injury - etiology</subject><subject>Acute Kidney Injury - metabolism</subject><subject>Acute Kidney Injury - pathology</subject><subject>Animals</subject><subject>Antihypertensive Agents - pharmacology</subject><subject>Biomarkers - metabolism</subject><subject>Blood Urea Nitrogen</subject><subject>Caspase 3 - metabolism</subject><subject>Creatinine - blood</subject><subject>Disease Models, Animal</subject><subject>Epoprostenol - analogs & derivatives</subject><subject>Epoprostenol - pharmacology</subject><subject>Interleukin-1beta - metabolism</subject><subject>Kidney Function Tests</subject><subject>Lipocalin-2 - metabolism</subject><subject>Male</subject><subject>ORIGINAL ARTICLES</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion Injury - complications</subject><issn>0931-0509</issn><issn>1460-2385</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU2LFDEQhoMo7rh68i45CtpuPjrdiQdBFr9gwct6DjVJ9WzWdDIm3cL8CP-zGXdc9FRU1fs-CfUS8pyzN5wZeZH8crGbAIQcHpAN7wfWCanVQ7JpW94xxcwZeVLrLWPMiHF8TM6k5GowQmzIr-uC-5LrElKIrynQPw24g4shUUgQ866NZ4whF1iw0oJtSEN1NzgH6Jody7TWkBMN6XYth7eNgUd7cE1Yl9WHZjvSaCPQOXuMNE8U3Log_R58wsPJ-pQ8miBWfHaq5-Tbxw_Xl5-7q6-fvly-v-qc1Hzp_CTktjdObwUTzgyOcecHNynQistBM5A9Y56jxl5qo-XgmerBKeGN4kzLc_LujrtftzN6h2kpEO2-hBnKwWYI9v9NCjd2l3_aUctembEBXp4AJf9YsS52bhfBGCFhXqsVvdKj0KMxTfrqTuraZWvB6f4ZzuwxQNsCtKcAm_rFvz-71_5NTP4Gtkqb-g</recordid><startdate>20210125</startdate><enddate>20210125</enddate><creator>Ding, Meiwen</creator><creator>Tolbert, Evelyn</creator><creator>Birkenbach, Mark</creator><creator>Akhlaghi, Fatemeh</creator><creator>Gohh, Reginald</creator><creator>Ghonem, Nisanne S</creator><general>Oxford University Press</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><orcidid>https://orcid.org/0000-0002-4724-0576</orcidid></search><sort><creationdate>20210125</creationdate><title>Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury</title><author>Ding, Meiwen ; Tolbert, Evelyn ; Birkenbach, Mark ; Akhlaghi, Fatemeh ; Gohh, Reginald ; Ghonem, Nisanne S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c381t-df23b49c8b202c96c01cd6cf5a8513680a3400d1e8e4389836d054ac52d951083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acute Kidney Injury - drug therapy</topic><topic>Acute Kidney Injury - etiology</topic><topic>Acute Kidney Injury - metabolism</topic><topic>Acute Kidney Injury - pathology</topic><topic>Animals</topic><topic>Antihypertensive Agents - pharmacology</topic><topic>Biomarkers - metabolism</topic><topic>Blood Urea Nitrogen</topic><topic>Caspase 3 - metabolism</topic><topic>Creatinine - blood</topic><topic>Disease Models, Animal</topic><topic>Epoprostenol - analogs & derivatives</topic><topic>Epoprostenol - pharmacology</topic><topic>Interleukin-1beta - metabolism</topic><topic>Kidney Function Tests</topic><topic>Lipocalin-2 - metabolism</topic><topic>Male</topic><topic>ORIGINAL ARTICLES</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reperfusion Injury - complications</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ding, Meiwen</creatorcontrib><creatorcontrib>Tolbert, Evelyn</creatorcontrib><creatorcontrib>Birkenbach, Mark</creatorcontrib><creatorcontrib>Akhlaghi, Fatemeh</creatorcontrib><creatorcontrib>Gohh, Reginald</creatorcontrib><creatorcontrib>Ghonem, Nisanne S</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>Nephrology, dialysis, transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ding, Meiwen</au><au>Tolbert, Evelyn</au><au>Birkenbach, Mark</au><au>Akhlaghi, Fatemeh</au><au>Gohh, Reginald</au><au>Ghonem, Nisanne S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury</atitle><jtitle>Nephrology, dialysis, transplantation</jtitle><addtitle>Nephrol Dial Transplant</addtitle><date>2021-01-25</date><risdate>2021</risdate><volume>36</volume><issue>2</issue><spage>257</spage><epage>266</epage><pages>257-266</pages><issn>0931-0509</issn><eissn>1460-2385</eissn><abstract>Renal ischemia-reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in vivo.
Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1-168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18-24 h before ischemia.
Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil.
This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>33156922</pmid><doi>10.1093/ndt/gfaa236</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-4724-0576</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Acute Kidney Injury - drug therapy Acute Kidney Injury - etiology Acute Kidney Injury - metabolism Acute Kidney Injury - pathology Animals Antihypertensive Agents - pharmacology Biomarkers - metabolism Blood Urea Nitrogen Caspase 3 - metabolism Creatinine - blood Disease Models, Animal Epoprostenol - analogs & derivatives Epoprostenol - pharmacology Interleukin-1beta - metabolism Kidney Function Tests Lipocalin-2 - metabolism Male ORIGINAL ARTICLES Rats Rats, Sprague-Dawley Reperfusion Injury - complications |
| title | Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury |
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