Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation
Lipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia). Increasing evidence suggests that fibroblast growth factor (FGF)21 has a crucial role in lipid metabolism under diabetic conditions. The present study inv...
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Veröffentlicht in: | PloS one 2013-12, Vol.8 (12), p.e82275 |
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creator | Zhang, Chi Shao, Minglong Yang, Hong Chen, Liangmiao Yu, Lechu Cong, Weitao Tian, Haishan Zhang, Fangfang Cheng, Peng Jin, Litai Tan, Yi Li, Xiaokun Cai, Lu Lu, Xuemian |
description | Lipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia). Increasing evidence suggests that fibroblast growth factor (FGF)21 has a crucial role in lipid metabolism under diabetic conditions.
The present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism.
Mice were injected with free fatty acids (FFAs, 10 mg/10 g body weight) or streptozotocin (150 mg/kg) to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 µg/kg) for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot.
Acute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21.
These results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis. |
doi_str_mv | 10.1371/journal.pone.0082275 |
format | Article |
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The present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism.
Mice were injected with free fatty acids (FFAs, 10 mg/10 g body weight) or streptozotocin (150 mg/kg) to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 µg/kg) for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot.
Acute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21.
These results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0082275</identifier><identifier>PMID: 24349242</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Accumulation ; Analysis ; Animal models ; Animals ; Apoptosis ; Apoptosis - drug effects ; Asian Americans ; B cells ; Body weight ; Cytokines ; Damage accumulation ; Damage prevention ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Experimental - pathology ; Diabetes Mellitus, Experimental - physiopathology ; Diabetic Nephropathies - complications ; Diabetic Nephropathies - drug therapy ; Diabetic Nephropathies - pathology ; Diabetic Nephropathies - physiopathology ; Enzyme-linked immunosorbent assay ; Fatty acids ; Fatty Acids - toxicity ; Fibroblast growth factors ; Fibroblast Growth Factors - administration & dosage ; Fibroblast Growth Factors - pharmacology ; Fibroblast Growth Factors - therapeutic use ; Fibroblasts ; Fibrosis ; Gene deletion ; Gene expression ; Glucose ; Growth factors ; Hyperlipidemia ; Hyperlipidemias - complications ; Hyperlipidemias - drug therapy ; Hyperlipidemias - pathology ; Hyperlipidemias - physiopathology ; Hypertrophy ; Inflammation ; Inflammation - complications ; Inflammation - drug therapy ; Inflammation - pathology ; Inflammation - physiopathology ; Insulin resistance ; Kidney - drug effects ; Kidney - pathology ; Kidney - physiopathology ; Kidney diseases ; Kinases ; Laboratory animals ; Lipid metabolism ; Lipid Metabolism - drug effects ; Lipids ; Male ; Metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardium - pathology ; Oxidative stress ; Oxidative Stress - drug effects ; Pathogenesis ; Pediatrics ; Pharmacy ; Physiological aspects ; Renal function ; Rodents ; Signal transduction ; Streptozocin ; Tibia ; Type 1 diabetes ; Type 2 diabetes</subject><ispartof>PloS one, 2013-12, Vol.8 (12), p.e82275</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/3.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Zhang et al 2013 Zhang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-266863f571ed1e1e7a0df006d67ddcc603c391c560d16566611c4843f43d67093</citedby><cites>FETCH-LOGICAL-c692t-266863f571ed1e1e7a0df006d67ddcc603c391c560d16566611c4843f43d67093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857822/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857822/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24349242$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Peng, Tianqing</contributor><creatorcontrib>Zhang, Chi</creatorcontrib><creatorcontrib>Shao, Minglong</creatorcontrib><creatorcontrib>Yang, Hong</creatorcontrib><creatorcontrib>Chen, Liangmiao</creatorcontrib><creatorcontrib>Yu, Lechu</creatorcontrib><creatorcontrib>Cong, Weitao</creatorcontrib><creatorcontrib>Tian, Haishan</creatorcontrib><creatorcontrib>Zhang, Fangfang</creatorcontrib><creatorcontrib>Cheng, Peng</creatorcontrib><creatorcontrib>Jin, Litai</creatorcontrib><creatorcontrib>Tan, Yi</creatorcontrib><creatorcontrib>Li, Xiaokun</creatorcontrib><creatorcontrib>Cai, Lu</creatorcontrib><creatorcontrib>Lu, Xuemian</creatorcontrib><title>Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Lipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia). Increasing evidence suggests that fibroblast growth factor (FGF)21 has a crucial role in lipid metabolism under diabetic conditions.
The present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism.
Mice were injected with free fatty acids (FFAs, 10 mg/10 g body weight) or streptozotocin (150 mg/kg) to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 µg/kg) for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot.
Acute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21.
These results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis.</description><subject>Accumulation</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Asian Americans</subject><subject>B cells</subject><subject>Body weight</subject><subject>Cytokines</subject><subject>Damage accumulation</subject><subject>Damage prevention</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetes Mellitus, Experimental - physiopathology</subject><subject>Diabetic Nephropathies - complications</subject><subject>Diabetic Nephropathies - drug therapy</subject><subject>Diabetic Nephropathies - pathology</subject><subject>Diabetic Nephropathies - physiopathology</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Fatty acids</subject><subject>Fatty Acids - toxicity</subject><subject>Fibroblast growth factors</subject><subject>Fibroblast Growth Factors - administration & dosage</subject><subject>Fibroblast Growth Factors - pharmacology</subject><subject>Fibroblast Growth Factors - therapeutic use</subject><subject>Fibroblasts</subject><subject>Fibrosis</subject><subject>Gene deletion</subject><subject>Gene expression</subject><subject>Glucose</subject><subject>Growth factors</subject><subject>Hyperlipidemia</subject><subject>Hyperlipidemias - complications</subject><subject>Hyperlipidemias - drug therapy</subject><subject>Hyperlipidemias - pathology</subject><subject>Hyperlipidemias - physiopathology</subject><subject>Hypertrophy</subject><subject>Inflammation</subject><subject>Inflammation - complications</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - pathology</subject><subject>Inflammation - physiopathology</subject><subject>Insulin resistance</subject><subject>Kidney - drug effects</subject><subject>Kidney - pathology</subject><subject>Kidney - physiopathology</subject><subject>Kidney diseases</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Lipid metabolism</subject><subject>Lipid Metabolism - drug effects</subject><subject>Lipids</subject><subject>Male</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocardium - pathology</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Pathogenesis</subject><subject>Pediatrics</subject><subject>Pharmacy</subject><subject>Physiological aspects</subject><subject>Renal function</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Streptozocin</subject><subject>Tibia</subject><subject>Type 1 diabetes</subject><subject>Type 2 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of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation</title><author>Zhang, Chi ; Shao, Minglong ; Yang, Hong ; Chen, Liangmiao ; Yu, Lechu ; Cong, Weitao ; Tian, Haishan ; Zhang, Fangfang ; Cheng, Peng ; Jin, Litai ; Tan, Yi ; Li, Xiaokun ; Cai, Lu ; Lu, Xuemian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-266863f571ed1e1e7a0df006d67ddcc603c391c560d16566611c4843f43d67093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Accumulation</topic><topic>Analysis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Asian Americans</topic><topic>B cells</topic><topic>Body weight</topic><topic>Cytokines</topic><topic>Damage accumulation</topic><topic>Damage prevention</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - complications</topic><topic>Diabetes Mellitus, Experimental - drug therapy</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Diabetes Mellitus, Experimental - physiopathology</topic><topic>Diabetic Nephropathies - complications</topic><topic>Diabetic Nephropathies - drug therapy</topic><topic>Diabetic Nephropathies - pathology</topic><topic>Diabetic Nephropathies - physiopathology</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Fatty acids</topic><topic>Fatty Acids - toxicity</topic><topic>Fibroblast growth factors</topic><topic>Fibroblast Growth Factors - administration & dosage</topic><topic>Fibroblast Growth Factors - pharmacology</topic><topic>Fibroblast Growth Factors - therapeutic use</topic><topic>Fibroblasts</topic><topic>Fibrosis</topic><topic>Gene deletion</topic><topic>Gene expression</topic><topic>Glucose</topic><topic>Growth 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Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Chi</au><au>Shao, Minglong</au><au>Yang, Hong</au><au>Chen, Liangmiao</au><au>Yu, Lechu</au><au>Cong, Weitao</au><au>Tian, Haishan</au><au>Zhang, Fangfang</au><au>Cheng, Peng</au><au>Jin, Litai</au><au>Tan, Yi</au><au>Li, Xiaokun</au><au>Cai, Lu</au><au>Lu, Xuemian</au><au>Peng, Tianqing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-12-09</date><risdate>2013</risdate><volume>8</volume><issue>12</issue><spage>e82275</spage><pages>e82275-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Lipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia). Increasing evidence suggests that fibroblast growth factor (FGF)21 has a crucial role in lipid metabolism under diabetic conditions.
The present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism.
Mice were injected with free fatty acids (FFAs, 10 mg/10 g body weight) or streptozotocin (150 mg/kg) to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 µg/kg) for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot.
Acute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21.
These results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24349242</pmid><doi>10.1371/journal.pone.0082275</doi><tpages>e82275</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2013-12, Vol.8 (12), p.e82275 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1466172378 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Accumulation Analysis Animal models Animals Apoptosis Apoptosis - drug effects Asian Americans B cells Body weight Cytokines Damage accumulation Damage prevention Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - complications Diabetes Mellitus, Experimental - drug therapy Diabetes Mellitus, Experimental - pathology Diabetes Mellitus, Experimental - physiopathology Diabetic Nephropathies - complications Diabetic Nephropathies - drug therapy Diabetic Nephropathies - pathology Diabetic Nephropathies - physiopathology Enzyme-linked immunosorbent assay Fatty acids Fatty Acids - toxicity Fibroblast growth factors Fibroblast Growth Factors - administration & dosage Fibroblast Growth Factors - pharmacology Fibroblast Growth Factors - therapeutic use Fibroblasts Fibrosis Gene deletion Gene expression Glucose Growth factors Hyperlipidemia Hyperlipidemias - complications Hyperlipidemias - drug therapy Hyperlipidemias - pathology Hyperlipidemias - physiopathology Hypertrophy Inflammation Inflammation - complications Inflammation - drug therapy Inflammation - pathology Inflammation - physiopathology Insulin resistance Kidney - drug effects Kidney - pathology Kidney - physiopathology Kidney diseases Kinases Laboratory animals Lipid metabolism Lipid Metabolism - drug effects Lipids Male Metabolism Mice Mice, Inbred C57BL Mice, Knockout Myocardium - pathology Oxidative stress Oxidative Stress - drug effects Pathogenesis Pediatrics Pharmacy Physiological aspects Renal function Rodents Signal transduction Streptozocin Tibia Type 1 diabetes Type 2 diabetes |
title | Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation |
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