Endogenous Relaxin Is a Naturally Occurring Modulator of Experimental Renal Tubulointerstitial Fibrosis

Relaxin is a naturally occurring regulator of collagen turnover. In this study, we determined the role of endogenous relaxin in the pathogenesis of primary tubulointerstitial fibrosis after unilateral ureteric obstruction (UUO). Four- to 6-wk-old relaxin (RLX) gene-knockout (RLX−/−) and age-matched...

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Veröffentlicht in:Endocrinology (Philadelphia) 2007-02, Vol.148 (2), p.660-669
Hauptverfasser: Hewitson, Tim D, Mookerjee, Ishanee, Masterson, Rosemary, Zhao, Chongxin, Tregear, Geoffrey W, Becker, Gavin J, Samuel, Chrishan S
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container_issue 2
container_start_page 660
container_title Endocrinology (Philadelphia)
container_volume 148
creator Hewitson, Tim D
Mookerjee, Ishanee
Masterson, Rosemary
Zhao, Chongxin
Tregear, Geoffrey W
Becker, Gavin J
Samuel, Chrishan S
description Relaxin is a naturally occurring regulator of collagen turnover. In this study, we determined the role of endogenous relaxin in the pathogenesis of primary tubulointerstitial fibrosis after unilateral ureteric obstruction (UUO). Four- to 6-wk-old relaxin (RLX) gene-knockout (RLX−/−) and age-matched wild-type (RLX+/+) mice, with equivalent baseline collagen levels, were subjected to UUO. Obstructed and contralateral kidneys were collected at d 0, 3, and 10 after surgery and analyzed for changes in inflammatory and fibrosis-related markers. UUO was associated with a progressive increase in fibrosis in all obstructed, but not contralateral kidneys. The increase in total collagen (hydroxyproline analysis) was associated with more α-smooth muscle actin (α-SMA) staining (myofibroblasts) and interstitial collagen sub-types (SDS-PAGE; types I, III, and V), whereas gelatin zymography demonstrated increased expression of matrix metalloproteinase-2 after surgery. By d 10 after UUO, there was a 5-fold decrease in RLX mRNA expression (quantitative RT-PCR) in RLX+/+ animals. Total collagen and α-SMA expression were significantly greater in the obstructed kidneys of RLX−/− mice 3 d after UUO (both P < 0.05 vs. RLX+/+ D3 after UUO), but comparable to that in RLX+/+ animals 10 d after UUO. Administration of recombinant H2 relaxin to RLX−/− mice 4 d before UUO ameliorated the increase in collagen and α-SMA expression (both P < 0.05 vs. untreated RLX−/− mice) by d 3 after UUO. Expression of monocyte chemoattractant protein-1 and macrophage infiltration (inflammation) in addition to that of matrix metalloproteinases was unaffected by genotype after UUO. These combined data demonstrate that endogenous RLX acts as a modulating factor in tubulointerstitial fibrosis, a hallmark of progressive renal disease. This is likely to be via direct effects on renal myofibroblast function.
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In this study, we determined the role of endogenous relaxin in the pathogenesis of primary tubulointerstitial fibrosis after unilateral ureteric obstruction (UUO). Four- to 6-wk-old relaxin (RLX) gene-knockout (RLX−/−) and age-matched wild-type (RLX+/+) mice, with equivalent baseline collagen levels, were subjected to UUO. Obstructed and contralateral kidneys were collected at d 0, 3, and 10 after surgery and analyzed for changes in inflammatory and fibrosis-related markers. UUO was associated with a progressive increase in fibrosis in all obstructed, but not contralateral kidneys. The increase in total collagen (hydroxyproline analysis) was associated with more α-smooth muscle actin (α-SMA) staining (myofibroblasts) and interstitial collagen sub-types (SDS-PAGE; types I, III, and V), whereas gelatin zymography demonstrated increased expression of matrix metalloproteinase-2 after surgery. By d 10 after UUO, there was a 5-fold decrease in RLX mRNA expression (quantitative RT-PCR) in RLX+/+ animals. Total collagen and α-SMA expression were significantly greater in the obstructed kidneys of RLX−/− mice 3 d after UUO (both P &lt; 0.05 vs. RLX+/+ D3 after UUO), but comparable to that in RLX+/+ animals 10 d after UUO. Administration of recombinant H2 relaxin to RLX−/− mice 4 d before UUO ameliorated the increase in collagen and α-SMA expression (both P &lt; 0.05 vs. untreated RLX−/− mice) by d 3 after UUO. Expression of monocyte chemoattractant protein-1 and macrophage infiltration (inflammation) in addition to that of matrix metalloproteinases was unaffected by genotype after UUO. These combined data demonstrate that endogenous RLX acts as a modulating factor in tubulointerstitial fibrosis, a hallmark of progressive renal disease. 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Psychology ; Gelatin ; Gene expression ; Genotypes ; Humans ; Hydroxyproline ; Kidney - metabolism ; Kidney Diseases - etiology ; Kidney Diseases - metabolism ; Kidney Diseases - pathology ; Kidney Tubules - pathology ; Kidneys ; Macrophages ; Matrix metalloproteinase ; Matrix Metalloproteinase 2 - metabolism ; Matrix Metalloproteinase 9 - metabolism ; Matrix metalloproteinases ; Medical sciences ; Metalloproteinase ; Mice ; Mice, Knockout ; Monocyte chemoattractant protein ; Monocyte chemoattractant protein 1 ; Monocytes ; Muscle, Smooth - metabolism ; Myocytes, Smooth Muscle - pathology ; Nephritis, Interstitial - etiology ; Nephritis, Interstitial - metabolism ; Nephritis, Interstitial - pathology ; Nephrology. Urinary tract diseases ; Osmolar Concentration ; Pathogenesis ; Recombinant Proteins - pharmacology ; Relaxin ; Relaxin - deficiency ; Relaxin - genetics ; Relaxin - metabolism ; Relaxin - pharmacology ; Renal function ; RNA, Messenger - metabolism ; Smooth muscle ; Surgery ; Ureter ; Ureteral Obstruction - complications ; Ureteral Obstruction - metabolism ; Urinary system involvement in other diseases. Miscellaneous ; Vertebrates: endocrinology</subject><ispartof>Endocrinology (Philadelphia), 2007-02, Vol.148 (2), p.660-669</ispartof><rights>Copyright © 2007 by the Endocrine Society 2007</rights><rights>2007 INIST-CNRS</rights><rights>Copyright © 2007 by the Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-1bed1a8c8c0f86268206e49645258466ece6c3c173367eabf356f173872be3b73</citedby><cites>FETCH-LOGICAL-c527t-1bed1a8c8c0f86268206e49645258466ece6c3c173367eabf356f173872be3b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=18479307$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17095590$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hewitson, Tim D</creatorcontrib><creatorcontrib>Mookerjee, Ishanee</creatorcontrib><creatorcontrib>Masterson, Rosemary</creatorcontrib><creatorcontrib>Zhao, Chongxin</creatorcontrib><creatorcontrib>Tregear, Geoffrey W</creatorcontrib><creatorcontrib>Becker, Gavin J</creatorcontrib><creatorcontrib>Samuel, Chrishan S</creatorcontrib><title>Endogenous Relaxin Is a Naturally Occurring Modulator of Experimental Renal Tubulointerstitial Fibrosis</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>Relaxin is a naturally occurring regulator of collagen turnover. In this study, we determined the role of endogenous relaxin in the pathogenesis of primary tubulointerstitial fibrosis after unilateral ureteric obstruction (UUO). Four- to 6-wk-old relaxin (RLX) gene-knockout (RLX−/−) and age-matched wild-type (RLX+/+) mice, with equivalent baseline collagen levels, were subjected to UUO. Obstructed and contralateral kidneys were collected at d 0, 3, and 10 after surgery and analyzed for changes in inflammatory and fibrosis-related markers. UUO was associated with a progressive increase in fibrosis in all obstructed, but not contralateral kidneys. The increase in total collagen (hydroxyproline analysis) was associated with more α-smooth muscle actin (α-SMA) staining (myofibroblasts) and interstitial collagen sub-types (SDS-PAGE; types I, III, and V), whereas gelatin zymography demonstrated increased expression of matrix metalloproteinase-2 after surgery. By d 10 after UUO, there was a 5-fold decrease in RLX mRNA expression (quantitative RT-PCR) in RLX+/+ animals. Total collagen and α-SMA expression were significantly greater in the obstructed kidneys of RLX−/− mice 3 d after UUO (both P &lt; 0.05 vs. RLX+/+ D3 after UUO), but comparable to that in RLX+/+ animals 10 d after UUO. Administration of recombinant H2 relaxin to RLX−/− mice 4 d before UUO ameliorated the increase in collagen and α-SMA expression (both P &lt; 0.05 vs. untreated RLX−/− mice) by d 3 after UUO. Expression of monocyte chemoattractant protein-1 and macrophage infiltration (inflammation) in addition to that of matrix metalloproteinases was unaffected by genotype after UUO. These combined data demonstrate that endogenous RLX acts as a modulating factor in tubulointerstitial fibrosis, a hallmark of progressive renal disease. This is likely to be via direct effects on renal myofibroblast function.</description><subject>Actin</subject><subject>Actins - metabolism</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Collagen</subject><subject>Collagen - metabolism</subject><subject>Disease Progression</subject><subject>Fibroblasts - pathology</subject><subject>Fibrosis</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gelatin</subject><subject>Gene expression</subject><subject>Genotypes</subject><subject>Humans</subject><subject>Hydroxyproline</subject><subject>Kidney - metabolism</subject><subject>Kidney Diseases - etiology</subject><subject>Kidney Diseases - metabolism</subject><subject>Kidney Diseases - pathology</subject><subject>Kidney Tubules - pathology</subject><subject>Kidneys</subject><subject>Macrophages</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Matrix metalloproteinases</subject><subject>Medical sciences</subject><subject>Metalloproteinase</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Monocyte chemoattractant protein</subject><subject>Monocyte chemoattractant protein 1</subject><subject>Monocytes</subject><subject>Muscle, Smooth - metabolism</subject><subject>Myocytes, Smooth Muscle - pathology</subject><subject>Nephritis, Interstitial - etiology</subject><subject>Nephritis, Interstitial - metabolism</subject><subject>Nephritis, Interstitial - pathology</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Osmolar Concentration</subject><subject>Pathogenesis</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Relaxin</subject><subject>Relaxin - deficiency</subject><subject>Relaxin - genetics</subject><subject>Relaxin - metabolism</subject><subject>Relaxin - pharmacology</subject><subject>Renal function</subject><subject>RNA, Messenger - metabolism</subject><subject>Smooth muscle</subject><subject>Surgery</subject><subject>Ureter</subject><subject>Ureteral Obstruction - complications</subject><subject>Ureteral Obstruction - metabolism</subject><subject>Urinary system involvement in other diseases. 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Psychology</topic><topic>Gelatin</topic><topic>Gene expression</topic><topic>Genotypes</topic><topic>Humans</topic><topic>Hydroxyproline</topic><topic>Kidney - metabolism</topic><topic>Kidney Diseases - etiology</topic><topic>Kidney Diseases - metabolism</topic><topic>Kidney Diseases - pathology</topic><topic>Kidney Tubules - pathology</topic><topic>Kidneys</topic><topic>Macrophages</topic><topic>Matrix metalloproteinase</topic><topic>Matrix Metalloproteinase 2 - metabolism</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Matrix metalloproteinases</topic><topic>Medical sciences</topic><topic>Metalloproteinase</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Monocyte chemoattractant protein</topic><topic>Monocyte chemoattractant protein 1</topic><topic>Monocytes</topic><topic>Muscle, Smooth - metabolism</topic><topic>Myocytes, Smooth Muscle - pathology</topic><topic>Nephritis, Interstitial - etiology</topic><topic>Nephritis, Interstitial - metabolism</topic><topic>Nephritis, Interstitial - pathology</topic><topic>Nephrology. 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In this study, we determined the role of endogenous relaxin in the pathogenesis of primary tubulointerstitial fibrosis after unilateral ureteric obstruction (UUO). Four- to 6-wk-old relaxin (RLX) gene-knockout (RLX−/−) and age-matched wild-type (RLX+/+) mice, with equivalent baseline collagen levels, were subjected to UUO. Obstructed and contralateral kidneys were collected at d 0, 3, and 10 after surgery and analyzed for changes in inflammatory and fibrosis-related markers. UUO was associated with a progressive increase in fibrosis in all obstructed, but not contralateral kidneys. The increase in total collagen (hydroxyproline analysis) was associated with more α-smooth muscle actin (α-SMA) staining (myofibroblasts) and interstitial collagen sub-types (SDS-PAGE; types I, III, and V), whereas gelatin zymography demonstrated increased expression of matrix metalloproteinase-2 after surgery. By d 10 after UUO, there was a 5-fold decrease in RLX mRNA expression (quantitative RT-PCR) in RLX+/+ animals. Total collagen and α-SMA expression were significantly greater in the obstructed kidneys of RLX−/− mice 3 d after UUO (both P &lt; 0.05 vs. RLX+/+ D3 after UUO), but comparable to that in RLX+/+ animals 10 d after UUO. Administration of recombinant H2 relaxin to RLX−/− mice 4 d before UUO ameliorated the increase in collagen and α-SMA expression (both P &lt; 0.05 vs. untreated RLX−/− mice) by d 3 after UUO. Expression of monocyte chemoattractant protein-1 and macrophage infiltration (inflammation) in addition to that of matrix metalloproteinases was unaffected by genotype after UUO. These combined data demonstrate that endogenous RLX acts as a modulating factor in tubulointerstitial fibrosis, a hallmark of progressive renal disease. This is likely to be via direct effects on renal myofibroblast function.</abstract><cop>Bethesda, MD</cop><pub>Endocrine Society</pub><pmid>17095590</pmid><doi>10.1210/en.2006-0814</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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source Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
subjects Actin
Actins - metabolism
Animals
Biological and medical sciences
Collagen
Collagen - metabolism
Disease Progression
Fibroblasts - pathology
Fibrosis
Fundamental and applied biological sciences. Psychology
Gelatin
Gene expression
Genotypes
Humans
Hydroxyproline
Kidney - metabolism
Kidney Diseases - etiology
Kidney Diseases - metabolism
Kidney Diseases - pathology
Kidney Tubules - pathology
Kidneys
Macrophages
Matrix metalloproteinase
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - metabolism
Matrix metalloproteinases
Medical sciences
Metalloproteinase
Mice
Mice, Knockout
Monocyte chemoattractant protein
Monocyte chemoattractant protein 1
Monocytes
Muscle, Smooth - metabolism
Myocytes, Smooth Muscle - pathology
Nephritis, Interstitial - etiology
Nephritis, Interstitial - metabolism
Nephritis, Interstitial - pathology
Nephrology. Urinary tract diseases
Osmolar Concentration
Pathogenesis
Recombinant Proteins - pharmacology
Relaxin
Relaxin - deficiency
Relaxin - genetics
Relaxin - metabolism
Relaxin - pharmacology
Renal function
RNA, Messenger - metabolism
Smooth muscle
Surgery
Ureter
Ureteral Obstruction - complications
Ureteral Obstruction - metabolism
Urinary system involvement in other diseases. Miscellaneous
Vertebrates: endocrinology
title Endogenous Relaxin Is a Naturally Occurring Modulator of Experimental Renal Tubulointerstitial Fibrosis
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