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Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity: Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways
The calcineurin inhibitor tacrolimus is an effective and widely used immunosuppressant after organ transplantation to reduce graft rejection. However, its nephrotoxic effect could compel the patients to treatment discontinuation. The beneficial effects of angiotensin-converting enzyme 2 (ACE2) on th...
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| Published in: | Life sciences (1973) 2022-01, Vol.288, p.120154, Article 120154 |
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| container_start_page | 120154 |
| container_title | Life sciences (1973) |
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| creator | Azouz, Amany A. Omar, Hany A. Hersi, Fatema Ali, Fares E.M. Hussein Elkelawy, Asmaa Mohammed M. |
| description | The calcineurin inhibitor tacrolimus is an effective and widely used immunosuppressant after organ transplantation to reduce graft rejection. However, its nephrotoxic effect could compel the patients to treatment discontinuation. The beneficial effects of angiotensin-converting enzyme 2 (ACE2) on the kidney and other organs have been investigated in several studies, but its role in tacrolimus nephrotoxicity still needs to be elucidated. Our study was designed to investigate effects of the ACE2 activator xanthenone on tacrolimus-induced renal injury.
Male Wistar rats were administered xanthenone (2 mg/kg) concurrently with tacrolimus (1 mg/kg) for 3 weeks, then blood and kidney tissue samples were collected for biochemical and molecular investigations.
Co-administration of xanthenone significantly improved renal functions in tacrolimus-treated rats, where serum creatinine, urea, and uric acid levels were close to those of the normal control. Besides, xanthenone reduced renal angiotensin (ANG) II content, while elevated ANG (1–7). Relative protein expressions of p-ERK/ERK and p-p38 MAPK/p38 MAPK inflammatory signals were downregulated upon xanthenone administration with tacrolimus. In addition, xanthenone reinforced antioxidant defense against tacrolimus by enhancing protein expression of the transcription factor Nrf2 with subsequently increased mRNA expressions of the antioxidants SOD3 and GCLC.
These protective effects of xanthenone could be attributed to ANG II degradation to ANG (1–7) by ACE2 activation resulting in regulated inflammatory and oxidative responses in the kidney. Therefore, administration of xanthenone along with tacrolimus could be a promising therapeutic strategy to reduce the adverse effects and increase the tolerability to tacrolimus immunosuppressive therapy.
[Display omitted]
•Tacrolimus induces renal injury via activation of uric acid/ERK/p38 MAPK pathway.•Xanthenone retards the elevation of uric acid, urea, and creatinine by tacrolimus.•Xanthenone reduces renal ANG II and elevates ANG (1–7) in tacrolimus-treated rats.•Xanthenone attenuates ERK/p38 MAPK signaling activation in tacrolimus-treated rats.•Xanthenone enhances the antioxidant defense via Nrf2/SOD3/GCLC signaling. |
| doi_str_mv | 10.1016/j.lfs.2021.120154 |
| format | article |
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Male Wistar rats were administered xanthenone (2 mg/kg) concurrently with tacrolimus (1 mg/kg) for 3 weeks, then blood and kidney tissue samples were collected for biochemical and molecular investigations.
Co-administration of xanthenone significantly improved renal functions in tacrolimus-treated rats, where serum creatinine, urea, and uric acid levels were close to those of the normal control. Besides, xanthenone reduced renal angiotensin (ANG) II content, while elevated ANG (1–7). Relative protein expressions of p-ERK/ERK and p-p38 MAPK/p38 MAPK inflammatory signals were downregulated upon xanthenone administration with tacrolimus. In addition, xanthenone reinforced antioxidant defense against tacrolimus by enhancing protein expression of the transcription factor Nrf2 with subsequently increased mRNA expressions of the antioxidants SOD3 and GCLC.
These protective effects of xanthenone could be attributed to ANG II degradation to ANG (1–7) by ACE2 activation resulting in regulated inflammatory and oxidative responses in the kidney. Therefore, administration of xanthenone along with tacrolimus could be a promising therapeutic strategy to reduce the adverse effects and increase the tolerability to tacrolimus immunosuppressive therapy.
[Display omitted]
•Tacrolimus induces renal injury via activation of uric acid/ERK/p38 MAPK pathway.•Xanthenone retards the elevation of uric acid, urea, and creatinine by tacrolimus.•Xanthenone reduces renal ANG II and elevates ANG (1–7) in tacrolimus-treated rats.•Xanthenone attenuates ERK/p38 MAPK signaling activation in tacrolimus-treated rats.•Xanthenone enhances the antioxidant defense via Nrf2/SOD3/GCLC signaling.</description><identifier>ISSN: 0024-3205</identifier><identifier>EISSN: 1879-0631</identifier><identifier>DOI: 10.1016/j.lfs.2021.120154</identifier><identifier>PMID: 34800514</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>ACE2 ; ACE2 activation ; Angiotensin ; Angiotensin II ; Angiotensin II - genetics ; Angiotensin II - metabolism ; Angiotensin-converting enzyme 2 ; Angiotensin-Converting Enzyme 2 - metabolism ; Animals ; Antioxidants ; Calcineurin ; Calcineurin inhibitors ; Calcineurin Inhibitors - toxicity ; Creatinine ; Enzyme Activation ; ERK/p38 MAPK ; Extracellular signal-regulated kinase ; Extracellular Signal-Regulated MAP Kinases - genetics ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Gene Expression Regulation - drug effects ; Glutamate-Cysteine Ligase - genetics ; Glutamate-Cysteine Ligase - metabolism ; Graft rejection ; Immunosuppressive agents ; Inflammation ; Kidney Diseases - chemically induced ; Kidney Diseases - drug therapy ; Kidney Diseases - metabolism ; Kidney Diseases - pathology ; Kidneys ; Male ; MAP kinase ; NF-E2-Related Factor 2 - genetics ; NF-E2-Related Factor 2 - metabolism ; Nrf2/SOD3/GCLC ; Organs ; p38 Mitogen-Activated Protein Kinases - genetics ; p38 Mitogen-Activated Protein Kinases - metabolism ; Peptidyl-dipeptidase A ; Proteins ; Rats ; Rats, Wistar ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism ; Tacrolimus ; Tacrolimus - toxicity ; Transplantation ; Urea ; Uric acid ; Uric Acid - metabolism ; Xanthenes - pharmacology ; Xanthenone</subject><ispartof>Life sciences (1973), 2022-01, Vol.288, p.120154, Article 120154</ispartof><rights>2021 Elsevier Inc.</rights><rights>Copyright © 2021 Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier BV Jan 1, 2022</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-7a52ea5d66a56655b2bea107e230006c84bc70328138dc907c9b9bc637e416c63</citedby><cites>FETCH-LOGICAL-c447t-7a52ea5d66a56655b2bea107e230006c84bc70328138dc907c9b9bc637e416c63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,783,787,27936,27937</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34800514$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Azouz, Amany A.</creatorcontrib><creatorcontrib>Omar, Hany A.</creatorcontrib><creatorcontrib>Hersi, Fatema</creatorcontrib><creatorcontrib>Ali, Fares E.M.</creatorcontrib><creatorcontrib>Hussein Elkelawy, Asmaa Mohammed M.</creatorcontrib><title>Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity: Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways</title><title>Life sciences (1973)</title><addtitle>Life Sci</addtitle><description>The calcineurin inhibitor tacrolimus is an effective and widely used immunosuppressant after organ transplantation to reduce graft rejection. However, its nephrotoxic effect could compel the patients to treatment discontinuation. The beneficial effects of angiotensin-converting enzyme 2 (ACE2) on the kidney and other organs have been investigated in several studies, but its role in tacrolimus nephrotoxicity still needs to be elucidated. Our study was designed to investigate effects of the ACE2 activator xanthenone on tacrolimus-induced renal injury.
Male Wistar rats were administered xanthenone (2 mg/kg) concurrently with tacrolimus (1 mg/kg) for 3 weeks, then blood and kidney tissue samples were collected for biochemical and molecular investigations.
Co-administration of xanthenone significantly improved renal functions in tacrolimus-treated rats, where serum creatinine, urea, and uric acid levels were close to those of the normal control. Besides, xanthenone reduced renal angiotensin (ANG) II content, while elevated ANG (1–7). Relative protein expressions of p-ERK/ERK and p-p38 MAPK/p38 MAPK inflammatory signals were downregulated upon xanthenone administration with tacrolimus. In addition, xanthenone reinforced antioxidant defense against tacrolimus by enhancing protein expression of the transcription factor Nrf2 with subsequently increased mRNA expressions of the antioxidants SOD3 and GCLC.
These protective effects of xanthenone could be attributed to ANG II degradation to ANG (1–7) by ACE2 activation resulting in regulated inflammatory and oxidative responses in the kidney. Therefore, administration of xanthenone along with tacrolimus could be a promising therapeutic strategy to reduce the adverse effects and increase the tolerability to tacrolimus immunosuppressive therapy.
[Display omitted]
•Tacrolimus induces renal injury via activation of uric acid/ERK/p38 MAPK pathway.•Xanthenone retards the elevation of uric acid, urea, and creatinine by tacrolimus.•Xanthenone reduces renal ANG II and elevates ANG (1–7) in tacrolimus-treated rats.•Xanthenone attenuates ERK/p38 MAPK signaling activation in tacrolimus-treated rats.•Xanthenone enhances the antioxidant defense via Nrf2/SOD3/GCLC signaling.</description><subject>ACE2</subject><subject>ACE2 activation</subject><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Angiotensin II - genetics</subject><subject>Angiotensin II - metabolism</subject><subject>Angiotensin-converting enzyme 2</subject><subject>Angiotensin-Converting Enzyme 2 - metabolism</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Calcineurin</subject><subject>Calcineurin inhibitors</subject><subject>Calcineurin Inhibitors - toxicity</subject><subject>Creatinine</subject><subject>Enzyme Activation</subject><subject>ERK/p38 MAPK</subject><subject>Extracellular signal-regulated kinase</subject><subject>Extracellular Signal-Regulated MAP Kinases - genetics</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Glutamate-Cysteine Ligase - genetics</subject><subject>Glutamate-Cysteine Ligase - metabolism</subject><subject>Graft rejection</subject><subject>Immunosuppressive agents</subject><subject>Inflammation</subject><subject>Kidney Diseases - chemically induced</subject><subject>Kidney Diseases - drug therapy</subject><subject>Kidney Diseases - metabolism</subject><subject>Kidney Diseases - pathology</subject><subject>Kidneys</subject><subject>Male</subject><subject>MAP kinase</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nrf2/SOD3/GCLC</subject><subject>Organs</subject><subject>p38 Mitogen-Activated Protein Kinases - genetics</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Peptidyl-dipeptidase A</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase - metabolism</subject><subject>Tacrolimus</subject><subject>Tacrolimus - toxicity</subject><subject>Transplantation</subject><subject>Urea</subject><subject>Uric acid</subject><subject>Uric Acid - metabolism</subject><subject>Xanthenes - pharmacology</subject><subject>Xanthenone</subject><issn>0024-3205</issn><issn>1879-0631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kctu2zAQRYmiQeOk_YBuCgJdy-KbcrsyVCcN4jRFH2uCoqiYhiyqJJXEf5FPLg2nWXY1M8Sdg7m8ALzHaI4RFuV23ndxThDBc0wQ5uwVmOFKLgokKH4NZggRVlCC-Ck4i3GLEOJc0jfglLIq95jNwNPVbtQmQd_BtLFwWa8IzLO718kH-KiH_Dr4wUI_wKRN8L3bTREOdtwEn_yjMy7tP8Eb3069Ti6rMmkKzmSKa8vVj-typBW8WX6_hnpo4bfQkfLn7RdaXtbrGkZ3N-jeDXdw1GnzoPfxLTjpdB_tu-d6Dn5frH7VX4v17eVVvVwXhjGZCqk5sZq3QmguBOcNaazGSFpCs01hKtYYiSipMK1as0DSLJpFYwSVlmGR6zn4eOSOwf-ZbExq66eQj4mKiAxhRMqDCh9V2XmMwXZqDG6nw15hpA4ZqK3KGahDBuqYQd758Eyemp1tXzb-fXoWfD4KbPZ372xQ0Tg7GNu6YE1SrXf_wf8FcF-VVg</recordid><startdate>20220101</startdate><enddate>20220101</enddate><creator>Azouz, Amany A.</creator><creator>Omar, Hany A.</creator><creator>Hersi, Fatema</creator><creator>Ali, Fares E.M.</creator><creator>Hussein Elkelawy, Asmaa Mohammed M.</creator><general>Elsevier Inc</general><general>Elsevier BV</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20220101</creationdate><title>Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity: Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways</title><author>Azouz, Amany A. ; Omar, Hany A. ; Hersi, Fatema ; Ali, Fares E.M. ; Hussein Elkelawy, Asmaa Mohammed M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-7a52ea5d66a56655b2bea107e230006c84bc70328138dc907c9b9bc637e416c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>ACE2</topic><topic>ACE2 activation</topic><topic>Angiotensin</topic><topic>Angiotensin II</topic><topic>Angiotensin II - genetics</topic><topic>Angiotensin II - metabolism</topic><topic>Angiotensin-converting enzyme 2</topic><topic>Angiotensin-Converting Enzyme 2 - metabolism</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Calcineurin</topic><topic>Calcineurin inhibitors</topic><topic>Calcineurin Inhibitors - toxicity</topic><topic>Creatinine</topic><topic>Enzyme Activation</topic><topic>ERK/p38 MAPK</topic><topic>Extracellular signal-regulated kinase</topic><topic>Extracellular Signal-Regulated MAP Kinases - genetics</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Glutamate-Cysteine Ligase - genetics</topic><topic>Glutamate-Cysteine Ligase - metabolism</topic><topic>Graft rejection</topic><topic>Immunosuppressive agents</topic><topic>Inflammation</topic><topic>Kidney Diseases - chemically induced</topic><topic>Kidney Diseases - drug therapy</topic><topic>Kidney Diseases - metabolism</topic><topic>Kidney Diseases - pathology</topic><topic>Kidneys</topic><topic>Male</topic><topic>MAP kinase</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Nrf2/SOD3/GCLC</topic><topic>Organs</topic><topic>p38 Mitogen-Activated Protein Kinases - genetics</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Peptidyl-dipeptidase A</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Superoxide Dismutase - genetics</topic><topic>Superoxide Dismutase - metabolism</topic><topic>Tacrolimus</topic><topic>Tacrolimus - toxicity</topic><topic>Transplantation</topic><topic>Urea</topic><topic>Uric acid</topic><topic>Uric Acid - metabolism</topic><topic>Xanthenes - pharmacology</topic><topic>Xanthenone</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Azouz, Amany A.</creatorcontrib><creatorcontrib>Omar, Hany A.</creatorcontrib><creatorcontrib>Hersi, Fatema</creatorcontrib><creatorcontrib>Ali, Fares E.M.</creatorcontrib><creatorcontrib>Hussein Elkelawy, Asmaa Mohammed M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Life sciences (1973)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Azouz, Amany A.</au><au>Omar, Hany A.</au><au>Hersi, Fatema</au><au>Ali, Fares E.M.</au><au>Hussein Elkelawy, Asmaa Mohammed M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity: Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways</atitle><jtitle>Life sciences (1973)</jtitle><addtitle>Life Sci</addtitle><date>2022-01-01</date><risdate>2022</risdate><volume>288</volume><spage>120154</spage><pages>120154-</pages><artnum>120154</artnum><issn>0024-3205</issn><eissn>1879-0631</eissn><abstract>The calcineurin inhibitor tacrolimus is an effective and widely used immunosuppressant after organ transplantation to reduce graft rejection. However, its nephrotoxic effect could compel the patients to treatment discontinuation. The beneficial effects of angiotensin-converting enzyme 2 (ACE2) on the kidney and other organs have been investigated in several studies, but its role in tacrolimus nephrotoxicity still needs to be elucidated. Our study was designed to investigate effects of the ACE2 activator xanthenone on tacrolimus-induced renal injury.
Male Wistar rats were administered xanthenone (2 mg/kg) concurrently with tacrolimus (1 mg/kg) for 3 weeks, then blood and kidney tissue samples were collected for biochemical and molecular investigations.
Co-administration of xanthenone significantly improved renal functions in tacrolimus-treated rats, where serum creatinine, urea, and uric acid levels were close to those of the normal control. Besides, xanthenone reduced renal angiotensin (ANG) II content, while elevated ANG (1–7). Relative protein expressions of p-ERK/ERK and p-p38 MAPK/p38 MAPK inflammatory signals were downregulated upon xanthenone administration with tacrolimus. In addition, xanthenone reinforced antioxidant defense against tacrolimus by enhancing protein expression of the transcription factor Nrf2 with subsequently increased mRNA expressions of the antioxidants SOD3 and GCLC.
These protective effects of xanthenone could be attributed to ANG II degradation to ANG (1–7) by ACE2 activation resulting in regulated inflammatory and oxidative responses in the kidney. Therefore, administration of xanthenone along with tacrolimus could be a promising therapeutic strategy to reduce the adverse effects and increase the tolerability to tacrolimus immunosuppressive therapy.
[Display omitted]
•Tacrolimus induces renal injury via activation of uric acid/ERK/p38 MAPK pathway.•Xanthenone retards the elevation of uric acid, urea, and creatinine by tacrolimus.•Xanthenone reduces renal ANG II and elevates ANG (1–7) in tacrolimus-treated rats.•Xanthenone attenuates ERK/p38 MAPK signaling activation in tacrolimus-treated rats.•Xanthenone enhances the antioxidant defense via Nrf2/SOD3/GCLC signaling.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>34800514</pmid><doi>10.1016/j.lfs.2021.120154</doi></addata></record> |
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| subjects | ACE2 ACE2 activation Angiotensin Angiotensin II Angiotensin II - genetics Angiotensin II - metabolism Angiotensin-converting enzyme 2 Angiotensin-Converting Enzyme 2 - metabolism Animals Antioxidants Calcineurin Calcineurin inhibitors Calcineurin Inhibitors - toxicity Creatinine Enzyme Activation ERK/p38 MAPK Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - genetics Extracellular Signal-Regulated MAP Kinases - metabolism Gene Expression Regulation - drug effects Glutamate-Cysteine Ligase - genetics Glutamate-Cysteine Ligase - metabolism Graft rejection Immunosuppressive agents Inflammation Kidney Diseases - chemically induced Kidney Diseases - drug therapy Kidney Diseases - metabolism Kidney Diseases - pathology Kidneys Male MAP kinase NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Nrf2/SOD3/GCLC Organs p38 Mitogen-Activated Protein Kinases - genetics p38 Mitogen-Activated Protein Kinases - metabolism Peptidyl-dipeptidase A Proteins Rats Rats, Wistar Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Tacrolimus Tacrolimus - toxicity Transplantation Urea Uric acid Uric Acid - metabolism Xanthenes - pharmacology Xanthenone |
| title | Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity: Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways |
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