Characterization of the renal cortical transcriptome following Roux-en-Y gastric bypass surgery in experimental diabetic kidney disease
Introduction Roux-en-Y gastric bypass surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin t...
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| creator | Nair, Meera Martin, William P. Zhernovkov, Vadim Elliott, Jessie A. Fearon, Naomi Eckhardt, Hans McCormack, Janet Godson, Catherine Brennan, Eoin Patrick Marai, Mariam Fandriks, Lars Docherty, Neil G. le Roux, Carel W. |
| description | Introduction Roux-en-Y gastric bypass surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin these findings.
Research design and methods In adult male Zucker diabetic fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterize the transcriptional alterations governing the renal reparative response to RYGB.
Results In parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of transforming growth factor (TGF)-beta superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy.
Conclusions Improved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-beta-driven early profibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and type 2 diabetes. |
| doi_str_mv | 10.1136/bmjdrc-2019-001113 |
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Research design and methods In adult male Zucker diabetic fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterize the transcriptional alterations governing the renal reparative response to RYGB.
Results In parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of transforming growth factor (TGF)-beta superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy.
Conclusions Improved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-beta-driven early profibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and type 2 diabetes.</description><identifier>ISSN: 2052-4897</identifier><identifier>EISSN: 2052-4897</identifier><identifier>DOI: 10.1136/bmjdrc-2019-001113</identifier><identifier>PMID: 32747384</identifier><language>eng</language><publisher>LONDON: Bmj Publishing Group</publisher><subject>Animals ; Antibodies ; bariatric surgery ; complications ; Creatinine ; Diabetes ; Diabetic nephropathy ; Endocrinology & Metabolism ; Endocrinology and Diabetes ; Endokrinologi och diabetes ; excretion ; Gastrointestinal surgery ; glomerulus ; Glucose ; Growth factors ; Heart surgery ; Insulin ; kidney ; Kidney diseases ; Life Sciences & Biomedicine ; medical therapy ; metabolic surgery ; Metabolism ; mortality ; nephropathy ; Obesity ; outcomes ; pathology ; Pathophysiology/Complications ; rat(s) ; risk ; RNA studies ; Science & Technology ; type-2 ; Weight control ; ZDF</subject><ispartof>BMJ open diabetes research & care, 2020-07, Vol.8 (1), p.e001113, Article 001113</ispartof><rights>Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2020 Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>9</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000573837600044</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c534t-44370c9edd834f6a540ac8a338b2141ff426d1dae177f9cf505ba0289d421223</citedby><cites>FETCH-LOGICAL-c534t-44370c9edd834f6a540ac8a338b2141ff426d1dae177f9cf505ba0289d421223</cites><orcidid>0000-0001-5521-5445 ; 0000-0001-7005-3966 ; 0000-0003-4908-5474 ; 0000-0002-0961-2607 ; 0000-0001-6368-5295 ; 0000-0003-0736-3034</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398104/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398104/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2114,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32747384$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://gup.ub.gu.se/publication/296481$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Nair, Meera</creatorcontrib><creatorcontrib>Martin, William P.</creatorcontrib><creatorcontrib>Zhernovkov, Vadim</creatorcontrib><creatorcontrib>Elliott, Jessie A.</creatorcontrib><creatorcontrib>Fearon, Naomi</creatorcontrib><creatorcontrib>Eckhardt, Hans</creatorcontrib><creatorcontrib>McCormack, Janet</creatorcontrib><creatorcontrib>Godson, Catherine</creatorcontrib><creatorcontrib>Brennan, Eoin Patrick</creatorcontrib><creatorcontrib>Marai, Mariam</creatorcontrib><creatorcontrib>Fandriks, Lars</creatorcontrib><creatorcontrib>Docherty, Neil G.</creatorcontrib><creatorcontrib>le Roux, Carel W.</creatorcontrib><title>Characterization of the renal cortical transcriptome following Roux-en-Y gastric bypass surgery in experimental diabetic kidney disease</title><title>BMJ open diabetes research & care</title><addtitle>BMJ OPEN DIAB RES CA</addtitle><addtitle>BMJ Open Diabetes Res Care</addtitle><description>Introduction Roux-en-Y gastric bypass surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin these findings.
Research design and methods In adult male Zucker diabetic fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterize the transcriptional alterations governing the renal reparative response to RYGB.
Results In parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of transforming growth factor (TGF)-beta superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy.
Conclusions Improved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-beta-driven early profibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and type 2 diabetes.</description><subject>Animals</subject><subject>Antibodies</subject><subject>bariatric surgery</subject><subject>complications</subject><subject>Creatinine</subject><subject>Diabetes</subject><subject>Diabetic nephropathy</subject><subject>Endocrinology & Metabolism</subject><subject>Endocrinology and Diabetes</subject><subject>Endokrinologi och diabetes</subject><subject>excretion</subject><subject>Gastrointestinal surgery</subject><subject>glomerulus</subject><subject>Glucose</subject><subject>Growth factors</subject><subject>Heart surgery</subject><subject>Insulin</subject><subject>kidney</subject><subject>Kidney diseases</subject><subject>Life Sciences & Biomedicine</subject><subject>medical therapy</subject><subject>metabolic surgery</subject><subject>Metabolism</subject><subject>mortality</subject><subject>nephropathy</subject><subject>Obesity</subject><subject>outcomes</subject><subject>pathology</subject><subject>Pathophysiology/Complications</subject><subject>rat(s)</subject><subject>risk</subject><subject>RNA studies</subject><subject>Science & Technology</subject><subject>type-2</subject><subject>Weight 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Meera</creator><creator>Martin, William P.</creator><creator>Zhernovkov, Vadim</creator><creator>Elliott, Jessie A.</creator><creator>Fearon, Naomi</creator><creator>Eckhardt, Hans</creator><creator>McCormack, Janet</creator><creator>Godson, Catherine</creator><creator>Brennan, Eoin Patrick</creator><creator>Marai, Mariam</creator><creator>Fandriks, Lars</creator><creator>Docherty, Neil G.</creator><creator>le Roux, Carel W.</creator><general>Bmj Publishing Group</general><general>BMJ Publishing Group LTD</general><general>BMJ Publishing 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of the renal cortical transcriptome following Roux-en-Y gastric bypass surgery in experimental diabetic kidney disease</title><author>Nair, Meera ; Martin, William P. ; Zhernovkov, Vadim ; Elliott, Jessie A. ; Fearon, Naomi ; Eckhardt, Hans ; McCormack, Janet ; Godson, Catherine ; Brennan, Eoin Patrick ; Marai, Mariam ; Fandriks, Lars ; Docherty, Neil G. ; le Roux, Carel W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c534t-44370c9edd834f6a540ac8a338b2141ff426d1dae177f9cf505ba0289d421223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Antibodies</topic><topic>bariatric surgery</topic><topic>complications</topic><topic>Creatinine</topic><topic>Diabetes</topic><topic>Diabetic nephropathy</topic><topic>Endocrinology & Metabolism</topic><topic>Endocrinology and Diabetes</topic><topic>Endokrinologi och diabetes</topic><topic>excretion</topic><topic>Gastrointestinal surgery</topic><topic>glomerulus</topic><topic>Glucose</topic><topic>Growth factors</topic><topic>Heart surgery</topic><topic>Insulin</topic><topic>kidney</topic><topic>Kidney diseases</topic><topic>Life Sciences & Biomedicine</topic><topic>medical therapy</topic><topic>metabolic surgery</topic><topic>Metabolism</topic><topic>mortality</topic><topic>nephropathy</topic><topic>Obesity</topic><topic>outcomes</topic><topic>pathology</topic><topic>Pathophysiology/Complications</topic><topic>rat(s)</topic><topic>risk</topic><topic>RNA studies</topic><topic>Science & Technology</topic><topic>type-2</topic><topic>Weight control</topic><topic>ZDF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nair, Meera</creatorcontrib><creatorcontrib>Martin, William P.</creatorcontrib><creatorcontrib>Zhernovkov, Vadim</creatorcontrib><creatorcontrib>Elliott, Jessie 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W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of the renal cortical transcriptome following Roux-en-Y gastric bypass surgery in experimental diabetic kidney disease</atitle><jtitle>BMJ open diabetes research & care</jtitle><stitle>BMJ OPEN DIAB RES CA</stitle><addtitle>BMJ Open Diabetes Res Care</addtitle><date>2020-07</date><risdate>2020</risdate><volume>8</volume><issue>1</issue><spage>e001113</spage><pages>e001113-</pages><artnum>001113</artnum><issn>2052-4897</issn><eissn>2052-4897</eissn><abstract>Introduction Roux-en-Y gastric bypass surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin these findings.
Research design and methods In adult male Zucker diabetic fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterize the transcriptional alterations governing the renal reparative response to RYGB.
Results In parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of transforming growth factor (TGF)-beta superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy.
Conclusions Improved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-beta-driven early profibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and type 2 diabetes.</abstract><cop>LONDON</cop><pub>Bmj Publishing Group</pub><pmid>32747384</pmid><doi>10.1136/bmjdrc-2019-001113</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-5521-5445</orcidid><orcidid>https://orcid.org/0000-0001-7005-3966</orcidid><orcidid>https://orcid.org/0000-0003-4908-5474</orcidid><orcidid>https://orcid.org/0000-0002-0961-2607</orcidid><orcidid>https://orcid.org/0000-0001-6368-5295</orcidid><orcidid>https://orcid.org/0000-0003-0736-3034</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antibodies bariatric surgery complications Creatinine Diabetes Diabetic nephropathy Endocrinology & Metabolism Endocrinology and Diabetes Endokrinologi och diabetes excretion Gastrointestinal surgery glomerulus Glucose Growth factors Heart surgery Insulin kidney Kidney diseases Life Sciences & Biomedicine medical therapy metabolic surgery Metabolism mortality nephropathy Obesity outcomes pathology Pathophysiology/Complications rat(s) risk RNA studies Science & Technology type-2 Weight control ZDF |
| title | Characterization of the renal cortical transcriptome following Roux-en-Y gastric bypass surgery in experimental diabetic kidney disease |
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