Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance
Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podoc...
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| Veröffentlicht in: | Journal of the American Society of Nephrology 2007-09, Vol.18 (9), p.2554-2564 |
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| creator | NAKAJO, Aya KHOSHNOODI, Jamshid SWIATECKA-URBAN, Agnieszka TRYGGVASON, Karl YAN, Kunimasa TAKENAKA, Hitoshi HAGIWARA, Emi WATANABE, Takashi KAWAKAMI, Hayato KURAYAMA, Ryota SEKINE, Yuji BESSHO, Fumio TAKAHASHI, Shori |
| description | Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis. |
| doi_str_mv | 10.1681/asn.2006070732 |
| format | Article |
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When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.</description><identifier>ISSN: 1046-6673</identifier><identifier>EISSN: 1533-3450</identifier><identifier>DOI: 10.1681/asn.2006070732</identifier><identifier>PMID: 17687078</identifier><identifier>CODEN: JASNEU</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Adenosine Triphosphate - metabolism ; Animals ; Biological and medical sciences ; Cells, Cultured ; Endoplasmic Reticulum ; Energy Metabolism - drug effects ; Humans ; Immunosuppressive Agents - pharmacology ; IMP Dehydrogenase - antagonists & inhibitors ; IMP Dehydrogenase - genetics ; Intracellular Membranes - metabolism ; Kidney Glomerulus - metabolism ; Male ; Medical sciences ; Membrane Proteins - biosynthesis ; Membrane Proteins - drug effects ; Membrane Proteins - genetics ; Membrane Transport Proteins - metabolism ; Mice ; Nephrology. Urinary tract diseases ; Nephrotic Syndrome - complications ; Podocytes - metabolism ; Protein Processing, Post-Translational - drug effects ; Proteinuria - chemically induced ; Proteinuria - complications ; Puromycin Aminonucleoside ; Rats ; Rats, Sprague-Dawley ; Ribonucleosides - pharmacology ; RNA, Messenger - metabolism ; Stress, Physiological - etiology ; Stress, Physiological - physiopathology</subject><ispartof>Journal of the American Society of Nephrology, 2007-09, Vol.18 (9), p.2554-2564</ispartof><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c467t-270948f52fa035a31cca05c57af53500adc3546ed12eca502d016411b47f536b3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19042713$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17687078$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:116234527$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>NAKAJO, Aya</creatorcontrib><creatorcontrib>KHOSHNOODI, Jamshid</creatorcontrib><creatorcontrib>SWIATECKA-URBAN, Agnieszka</creatorcontrib><creatorcontrib>TRYGGVASON, Karl</creatorcontrib><creatorcontrib>YAN, Kunimasa</creatorcontrib><creatorcontrib>TAKENAKA, Hitoshi</creatorcontrib><creatorcontrib>HAGIWARA, Emi</creatorcontrib><creatorcontrib>WATANABE, Takashi</creatorcontrib><creatorcontrib>KAWAKAMI, Hayato</creatorcontrib><creatorcontrib>KURAYAMA, Ryota</creatorcontrib><creatorcontrib>SEKINE, Yuji</creatorcontrib><creatorcontrib>BESSHO, Fumio</creatorcontrib><creatorcontrib>TAKAHASHI, Shori</creatorcontrib><title>Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance</title><title>Journal of the American Society of Nephrology</title><addtitle>J Am Soc Nephrol</addtitle><description>Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Endoplasmic Reticulum</subject><subject>Energy Metabolism - drug effects</subject><subject>Humans</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>IMP Dehydrogenase - antagonists & inhibitors</subject><subject>IMP Dehydrogenase - genetics</subject><subject>Intracellular Membranes - metabolism</subject><subject>Kidney Glomerulus - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Proteins - biosynthesis</subject><subject>Membrane Proteins - drug effects</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Transport Proteins - metabolism</subject><subject>Mice</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Nephrotic Syndrome - complications</subject><subject>Podocytes - metabolism</subject><subject>Protein Processing, Post-Translational - drug effects</subject><subject>Proteinuria - chemically induced</subject><subject>Proteinuria - complications</subject><subject>Puromycin Aminonucleoside</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Ribonucleosides - pharmacology</subject><subject>RNA, Messenger - metabolism</subject><subject>Stress, Physiological - etiology</subject><subject>Stress, Physiological - physiopathology</subject><issn>1046-6673</issn><issn>1533-3450</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkD1PwzAQhi0EoqWwMiIvjCnn73SsKr6kAgOwsESOcymGNKnsFlR-PUaN6HSvTs9z0r2EnDMYM52zKxvbMQfQYMAIfkCGTAmRCangMGWQOtPaiAE5ifEDgCluzDEZMKPzJORD8vbgf7rgS98idV0I6NaRVlin6b-Qtrh6D76lpe8W2GL0kZZbGjCuk9QuqG_XwTpsmk1jA01EWGxpaRvbOjwlR7VtIp71c0Reb65fZnfZ_On2fjadZ05qs864gYnMa8VrC0JZwZyzoJwytlZCAdjKCSU1Voyjswp4BUxLxkppEqBLMSLZ7m78xtWmLFbBL23YFp31Rb_6TAkLpfNcisSPd7wLXYwB63-DQfFXajF9fiz2pSbhYiekU0us9njfYgIue8BGZ5s6pPd93HMTkNwwIX4BwhqBJA</recordid><startdate>20070901</startdate><enddate>20070901</enddate><creator>NAKAJO, Aya</creator><creator>KHOSHNOODI, Jamshid</creator><creator>SWIATECKA-URBAN, Agnieszka</creator><creator>TRYGGVASON, Karl</creator><creator>YAN, Kunimasa</creator><creator>TAKENAKA, Hitoshi</creator><creator>HAGIWARA, Emi</creator><creator>WATANABE, Takashi</creator><creator>KAWAKAMI, Hayato</creator><creator>KURAYAMA, Ryota</creator><creator>SEKINE, Yuji</creator><creator>BESSHO, Fumio</creator><creator>TAKAHASHI, Shori</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><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>ADTPV</scope><scope>AOWAS</scope></search><sort><creationdate>20070901</creationdate><title>Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance</title><author>NAKAJO, Aya ; KHOSHNOODI, Jamshid ; SWIATECKA-URBAN, Agnieszka ; TRYGGVASON, Karl ; YAN, Kunimasa ; TAKENAKA, Hitoshi ; HAGIWARA, Emi ; WATANABE, Takashi ; KAWAKAMI, Hayato ; KURAYAMA, Ryota ; SEKINE, Yuji ; BESSHO, Fumio ; TAKAHASHI, Shori</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c467t-270948f52fa035a31cca05c57af53500adc3546ed12eca502d016411b47f536b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Endoplasmic Reticulum</topic><topic>Energy Metabolism - drug effects</topic><topic>Humans</topic><topic>Immunosuppressive Agents - pharmacology</topic><topic>IMP Dehydrogenase - antagonists & inhibitors</topic><topic>IMP Dehydrogenase - genetics</topic><topic>Intracellular Membranes - metabolism</topic><topic>Kidney Glomerulus - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Proteins - biosynthesis</topic><topic>Membrane Proteins - drug effects</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Transport Proteins - metabolism</topic><topic>Mice</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Nephrotic Syndrome - complications</topic><topic>Podocytes - metabolism</topic><topic>Protein Processing, Post-Translational - drug effects</topic><topic>Proteinuria - chemically induced</topic><topic>Proteinuria - complications</topic><topic>Puromycin Aminonucleoside</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Ribonucleosides - pharmacology</topic><topic>RNA, Messenger - metabolism</topic><topic>Stress, Physiological - etiology</topic><topic>Stress, Physiological - physiopathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>NAKAJO, Aya</creatorcontrib><creatorcontrib>KHOSHNOODI, Jamshid</creatorcontrib><creatorcontrib>SWIATECKA-URBAN, Agnieszka</creatorcontrib><creatorcontrib>TRYGGVASON, Karl</creatorcontrib><creatorcontrib>YAN, Kunimasa</creatorcontrib><creatorcontrib>TAKENAKA, Hitoshi</creatorcontrib><creatorcontrib>HAGIWARA, Emi</creatorcontrib><creatorcontrib>WATANABE, Takashi</creatorcontrib><creatorcontrib>KAWAKAMI, Hayato</creatorcontrib><creatorcontrib>KURAYAMA, Ryota</creatorcontrib><creatorcontrib>SEKINE, Yuji</creatorcontrib><creatorcontrib>BESSHO, Fumio</creatorcontrib><creatorcontrib>TAKAHASHI, Shori</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>Journal of the American Society of Nephrology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>NAKAJO, Aya</au><au>KHOSHNOODI, Jamshid</au><au>SWIATECKA-URBAN, Agnieszka</au><au>TRYGGVASON, Karl</au><au>YAN, Kunimasa</au><au>TAKENAKA, Hitoshi</au><au>HAGIWARA, Emi</au><au>WATANABE, Takashi</au><au>KAWAKAMI, Hayato</au><au>KURAYAMA, Ryota</au><au>SEKINE, Yuji</au><au>BESSHO, Fumio</au><au>TAKAHASHI, Shori</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance</atitle><jtitle>Journal of the American Society of Nephrology</jtitle><addtitle>J Am Soc Nephrol</addtitle><date>2007-09-01</date><risdate>2007</risdate><volume>18</volume><issue>9</issue><spage>2554</spage><epage>2564</epage><pages>2554-2564</pages><issn>1046-6673</issn><eissn>1533-3450</eissn><coden>JASNEU</coden><abstract>Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>17687078</pmid><doi>10.1681/asn.2006070732</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1046-6673 |
| ispartof | Journal of the American Society of Nephrology, 2007-09, Vol.18 (9), p.2554-2564 |
| issn | 1046-6673 1533-3450 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adenosine Triphosphate - metabolism Animals Biological and medical sciences Cells, Cultured Endoplasmic Reticulum Energy Metabolism - drug effects Humans Immunosuppressive Agents - pharmacology IMP Dehydrogenase - antagonists & inhibitors IMP Dehydrogenase - genetics Intracellular Membranes - metabolism Kidney Glomerulus - metabolism Male Medical sciences Membrane Proteins - biosynthesis Membrane Proteins - drug effects Membrane Proteins - genetics Membrane Transport Proteins - metabolism Mice Nephrology. Urinary tract diseases Nephrotic Syndrome - complications Podocytes - metabolism Protein Processing, Post-Translational - drug effects Proteinuria - chemically induced Proteinuria - complications Puromycin Aminonucleoside Rats Rats, Sprague-Dawley Ribonucleosides - pharmacology RNA, Messenger - metabolism Stress, Physiological - etiology Stress, Physiological - physiopathology |
| title | Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance |
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