Altered aquaporin expression and role in apoptosis during hepatic stellate cell activation

Background: Hepatic stellate cells (HSCs) are effector cells of hepatic fibrosis contributing to excessive collagen deposition and scar matrix formation. Sustained HSC activation leads to hepatic cirrhosis, a leading cause of liver‐related death. Reversal of hepatic fibrosis has been attributed to t...

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Veröffentlicht in:Liver international 2011-01, Vol.31 (1), p.42-51
Hauptverfasser: Lakner, Ashley M., Walling, Tracy L., McKillop, Iain H., Schrum, Laura W.
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creator Lakner, Ashley M.
Walling, Tracy L.
McKillop, Iain H.
Schrum, Laura W.
description Background: Hepatic stellate cells (HSCs) are effector cells of hepatic fibrosis contributing to excessive collagen deposition and scar matrix formation. Sustained HSC activation leads to hepatic cirrhosis, a leading cause of liver‐related death. Reversal of hepatic fibrosis has been attributed to the induction of HSC apoptosis. Aquaporins (AQPs) are critical proteinacious channels that mediate cellular water loss during the initiation and progression of apoptosis. Aims: This study examined AQP expression in quiescent and activated HSCs and determined the responsiveness to AQP‐dependent apoptosis. Methods: Aquaporin gene and protein expressions in quiescent and activated HSCs were determined by reverse transcription polymerase chain reaction and Western blot analyses. AQP function was determined by cell swelling and apoptotic assays in the absence and presence of HgCl2, a non‐specific AQP inhibitor. Results: In this study, we report that activated HSCs showed no detectable expression of AQP 1, 5, 8, 9 and 12 mRNAs but expression was observed in quiescent HSCs. Similarly, AQP 0, 1, 8 and 9 protein was not detected in activated HSCs but was measured in quiescent HSCs. Dual fluorescent immunohistochemistry confirmed that AQP expression is decreased in activated HSCs in a model of liver injury. Functional studies demonstrated that quiescent HSCs were highly susceptible to osmotic challenge and apoptotic stimulus, whereas activated HSCs were less responsive. Finally, apoptosis was abrogated by the inhibition of AQP‐dependent water movement. Conclusions: These findings demonstrate that increased resistance to apoptosis in activated HSCs is due, at least in part, to the changes in AQP expression and function that occur following HSC activation.
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Sustained HSC activation leads to hepatic cirrhosis, a leading cause of liver‐related death. Reversal of hepatic fibrosis has been attributed to the induction of HSC apoptosis. Aquaporins (AQPs) are critical proteinacious channels that mediate cellular water loss during the initiation and progression of apoptosis. Aims: This study examined AQP expression in quiescent and activated HSCs and determined the responsiveness to AQP‐dependent apoptosis. Methods: Aquaporin gene and protein expressions in quiescent and activated HSCs were determined by reverse transcription polymerase chain reaction and Western blot analyses. AQP function was determined by cell swelling and apoptotic assays in the absence and presence of HgCl2, a non‐specific AQP inhibitor. Results: In this study, we report that activated HSCs showed no detectable expression of AQP 1, 5, 8, 9 and 12 mRNAs but expression was observed in quiescent HSCs. Similarly, AQP 0, 1, 8 and 9 protein was not detected in activated HSCs but was measured in quiescent HSCs. Dual fluorescent immunohistochemistry confirmed that AQP expression is decreased in activated HSCs in a model of liver injury. Functional studies demonstrated that quiescent HSCs were highly susceptible to osmotic challenge and apoptotic stimulus, whereas activated HSCs were less responsive. Finally, apoptosis was abrogated by the inhibition of AQP‐dependent water movement. Conclusions: These findings demonstrate that increased resistance to apoptosis in activated HSCs is due, at least in part, to the changes in AQP expression and function that occur following HSC activation.</description><identifier>ISSN: 1478-3223</identifier><identifier>EISSN: 1478-3231</identifier><identifier>DOI: 10.1111/j.1478-3231.2010.02356.x</identifier><identifier>PMID: 20958918</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; apoptosis ; Apoptosis - drug effects ; aquaporin ; Aquaporins - antagonists &amp; inhibitors ; Aquaporins - genetics ; Aquaporins - metabolism ; Blotting, Western ; Cell Membrane Permeability ; Cell Shape ; Cells, Cultured ; fibrosis ; Fluorescent Antibody Technique ; Gene Expression Regulation ; hepatic stellate cell ; Hepatic Stellate Cells - drug effects ; Hepatic Stellate Cells - metabolism ; Hepatic Stellate Cells - pathology ; Male ; Mercuric Chloride ; Osmosis ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - metabolism ; Time Factors ; transdifferentiation ; Water - metabolism</subject><ispartof>Liver international, 2011-01, Vol.31 (1), p.42-51</ispartof><rights>2010 John Wiley &amp; Sons A/S</rights><rights>2010 John Wiley &amp; Sons A/S.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4066-e4741821f6854ecda3fbc3fa27ea40968208eb84812ea1897975b47bf7f2f2a33</citedby><cites>FETCH-LOGICAL-c4066-e4741821f6854ecda3fbc3fa27ea40968208eb84812ea1897975b47bf7f2f2a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1478-3231.2010.02356.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1478-3231.2010.02356.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20958918$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lakner, Ashley M.</creatorcontrib><creatorcontrib>Walling, Tracy L.</creatorcontrib><creatorcontrib>McKillop, Iain H.</creatorcontrib><creatorcontrib>Schrum, Laura W.</creatorcontrib><title>Altered aquaporin expression and role in apoptosis during hepatic stellate cell activation</title><title>Liver international</title><addtitle>Liver Int</addtitle><description>Background: Hepatic stellate cells (HSCs) are effector cells of hepatic fibrosis contributing to excessive collagen deposition and scar matrix formation. Sustained HSC activation leads to hepatic cirrhosis, a leading cause of liver‐related death. Reversal of hepatic fibrosis has been attributed to the induction of HSC apoptosis. Aquaporins (AQPs) are critical proteinacious channels that mediate cellular water loss during the initiation and progression of apoptosis. Aims: This study examined AQP expression in quiescent and activated HSCs and determined the responsiveness to AQP‐dependent apoptosis. Methods: Aquaporin gene and protein expressions in quiescent and activated HSCs were determined by reverse transcription polymerase chain reaction and Western blot analyses. AQP function was determined by cell swelling and apoptotic assays in the absence and presence of HgCl2, a non‐specific AQP inhibitor. Results: In this study, we report that activated HSCs showed no detectable expression of AQP 1, 5, 8, 9 and 12 mRNAs but expression was observed in quiescent HSCs. Similarly, AQP 0, 1, 8 and 9 protein was not detected in activated HSCs but was measured in quiescent HSCs. Dual fluorescent immunohistochemistry confirmed that AQP expression is decreased in activated HSCs in a model of liver injury. Functional studies demonstrated that quiescent HSCs were highly susceptible to osmotic challenge and apoptotic stimulus, whereas activated HSCs were less responsive. Finally, apoptosis was abrogated by the inhibition of AQP‐dependent water movement. 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Sustained HSC activation leads to hepatic cirrhosis, a leading cause of liver‐related death. Reversal of hepatic fibrosis has been attributed to the induction of HSC apoptosis. Aquaporins (AQPs) are critical proteinacious channels that mediate cellular water loss during the initiation and progression of apoptosis. Aims: This study examined AQP expression in quiescent and activated HSCs and determined the responsiveness to AQP‐dependent apoptosis. Methods: Aquaporin gene and protein expressions in quiescent and activated HSCs were determined by reverse transcription polymerase chain reaction and Western blot analyses. AQP function was determined by cell swelling and apoptotic assays in the absence and presence of HgCl2, a non‐specific AQP inhibitor. Results: In this study, we report that activated HSCs showed no detectable expression of AQP 1, 5, 8, 9 and 12 mRNAs but expression was observed in quiescent HSCs. Similarly, AQP 0, 1, 8 and 9 protein was not detected in activated HSCs but was measured in quiescent HSCs. Dual fluorescent immunohistochemistry confirmed that AQP expression is decreased in activated HSCs in a model of liver injury. Functional studies demonstrated that quiescent HSCs were highly susceptible to osmotic challenge and apoptotic stimulus, whereas activated HSCs were less responsive. Finally, apoptosis was abrogated by the inhibition of AQP‐dependent water movement. Conclusions: These findings demonstrate that increased resistance to apoptosis in activated HSCs is due, at least in part, to the changes in AQP expression and function that occur following HSC activation.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>20958918</pmid><doi>10.1111/j.1478-3231.2010.02356.x</doi><tpages>10</tpages></addata></record>
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subjects Animals
apoptosis
Apoptosis - drug effects
aquaporin
Aquaporins - antagonists & inhibitors
Aquaporins - genetics
Aquaporins - metabolism
Blotting, Western
Cell Membrane Permeability
Cell Shape
Cells, Cultured
fibrosis
Fluorescent Antibody Technique
Gene Expression Regulation
hepatic stellate cell
Hepatic Stellate Cells - drug effects
Hepatic Stellate Cells - metabolism
Hepatic Stellate Cells - pathology
Male
Mercuric Chloride
Osmosis
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - metabolism
Time Factors
transdifferentiation
Water - metabolism
title Altered aquaporin expression and role in apoptosis during hepatic stellate cell activation
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