Podocytic PKC-alpha is regulated in murine and human diabetes and mediates nephrin endocytosis
Microalbuminuria is an early lesion during the development of diabetic nephropathy. The loss of high molecular weight proteins in the urine is usually associated with decreased expression of slit diaphragm proteins. Nephrin, is the major component of the glomerular slit diaphragm and loss of nephrin...
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| creator | Tossidou, Irini Teng, Beina Menne, Jan Shushakova, Nelli Park, Joon-Keun Becker, Jan U Modde, Friedrich Leitges, Michael Haller, Hermann Schiffer, Mario |
| description | Microalbuminuria is an early lesion during the development of diabetic nephropathy. The loss of high molecular weight proteins in the urine is usually associated with decreased expression of slit diaphragm proteins. Nephrin, is the major component of the glomerular slit diaphragm and loss of nephrin has been well described in rodent models of experimental diabetes as well as in human diabetic nephropathy.
In this manuscript we analyzed the role of PKC-alpha (PKCalpha) on endocytosis of nephrin in podocytes. We found that treatment of diabetic mice with a PKCalpha-inhibitor (GO6976) leads to preserved nephrin expression and reduced proteinuria. In vitro, we found that high glucose stimulation would induce PKCalpha protein expression in murine and human podocytes. We can demonstrate that PKCalpha mediates nephrin endocytosis in podocytes and that overexpression of PKCalpha leads to an augmented endocytosis response. After PKC-activation, we demonstrate an inducible association of PKCalpha, PICK1 and nephrin in podocytes. Moreover, we can demonstrate a strong induction of PKCalpha in podocytes of patients with diabetic nephropathy.
We therefore conclude that activation of PKCalpha is a pathomechanistic key event during the development of diabetic nephropathy. PKCalpha is involved in reduction of nephrin surface expression and therefore PKCalpha inhibition might be a novel target molecule for anti-proteinuric therapy. |
| doi_str_mv | 10.1371/journal.pone.0010185 |
| format | Article |
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In this manuscript we analyzed the role of PKC-alpha (PKCalpha) on endocytosis of nephrin in podocytes. We found that treatment of diabetic mice with a PKCalpha-inhibitor (GO6976) leads to preserved nephrin expression and reduced proteinuria. In vitro, we found that high glucose stimulation would induce PKCalpha protein expression in murine and human podocytes. We can demonstrate that PKCalpha mediates nephrin endocytosis in podocytes and that overexpression of PKCalpha leads to an augmented endocytosis response. After PKC-activation, we demonstrate an inducible association of PKCalpha, PICK1 and nephrin in podocytes. Moreover, we can demonstrate a strong induction of PKCalpha in podocytes of patients with diabetic nephropathy.
We therefore conclude that activation of PKCalpha is a pathomechanistic key event during the development of diabetic nephropathy. PKCalpha is involved in reduction of nephrin surface expression and therefore PKCalpha inhibition might be a novel target molecule for anti-proteinuric therapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0010185</identifier><identifier>PMID: 20419132</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Analysis ; Animal models ; Animals ; Biopsy ; Biotechnology ; Data analysis ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus - enzymology ; Diabetes Mellitus - metabolism ; Diabetic nephropathies ; Diabetic Nephropathies - etiology ; Diabetic Nephropathies - pathology ; Diabetic nephropathy ; Diaphragm (anatomy) ; Endocytosis ; Gene Expression Regulation, Enzymologic ; Glucose ; Glucose - pharmacology ; Humans ; Kinases ; Laboratories ; Ligands ; Mediation ; Medical schools ; Medicine ; Membrane Proteins - metabolism ; Mice ; Molecular weight ; Nephrology ; Nephrology/Chronic Kidney Disease ; Nephrology/Renal Physiology ; Nephropathy ; Pathology ; Podocytes - metabolism ; Podocytes - physiology ; Protein kinase C ; Protein Kinase C-alpha - genetics ; Protein Kinase C-alpha - metabolism ; Proteins ; Proteinuria ; Rodents ; Urine</subject><ispartof>PloS one, 2010-04, Vol.5 (4), p.e10185-e10185</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>2010 Tossidou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (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>Tossidou et al. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-28dac30e9ede38f643433b206b2f5f7b7566ac029facb0c18a1dc8668b8ae7ea3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855708/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855708/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20419132$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tossidou, Irini</creatorcontrib><creatorcontrib>Teng, Beina</creatorcontrib><creatorcontrib>Menne, Jan</creatorcontrib><creatorcontrib>Shushakova, Nelli</creatorcontrib><creatorcontrib>Park, Joon-Keun</creatorcontrib><creatorcontrib>Becker, Jan U</creatorcontrib><creatorcontrib>Modde, Friedrich</creatorcontrib><creatorcontrib>Leitges, Michael</creatorcontrib><creatorcontrib>Haller, Hermann</creatorcontrib><creatorcontrib>Schiffer, Mario</creatorcontrib><title>Podocytic PKC-alpha is regulated in murine and human diabetes and mediates nephrin endocytosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Microalbuminuria is an early lesion during the development of diabetic nephropathy. The loss of high molecular weight proteins in the urine is usually associated with decreased expression of slit diaphragm proteins. Nephrin, is the major component of the glomerular slit diaphragm and loss of nephrin has been well described in rodent models of experimental diabetes as well as in human diabetic nephropathy.
In this manuscript we analyzed the role of PKC-alpha (PKCalpha) on endocytosis of nephrin in podocytes. We found that treatment of diabetic mice with a PKCalpha-inhibitor (GO6976) leads to preserved nephrin expression and reduced proteinuria. In vitro, we found that high glucose stimulation would induce PKCalpha protein expression in murine and human podocytes. We can demonstrate that PKCalpha mediates nephrin endocytosis in podocytes and that overexpression of PKCalpha leads to an augmented endocytosis response. After PKC-activation, we demonstrate an inducible association of PKCalpha, PICK1 and nephrin in podocytes. Moreover, we can demonstrate a strong induction of PKCalpha in podocytes of patients with diabetic nephropathy.
We therefore conclude that activation of PKCalpha is a pathomechanistic key event during the development of diabetic nephropathy. PKCalpha is involved in reduction of nephrin surface expression and therefore PKCalpha inhibition might be a novel target molecule for anti-proteinuric therapy.</description><subject>Activation</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biopsy</subject><subject>Biotechnology</subject><subject>Data analysis</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus - enzymology</subject><subject>Diabetes Mellitus - metabolism</subject><subject>Diabetic nephropathies</subject><subject>Diabetic Nephropathies - etiology</subject><subject>Diabetic Nephropathies - pathology</subject><subject>Diabetic nephropathy</subject><subject>Diaphragm (anatomy)</subject><subject>Endocytosis</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Glucose</subject><subject>Glucose - pharmacology</subject><subject>Humans</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Ligands</subject><subject>Mediation</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Molecular weight</subject><subject>Nephrology</subject><subject>Nephrology/Chronic Kidney Disease</subject><subject>Nephrology/Renal Physiology</subject><subject>Nephropathy</subject><subject>Pathology</subject><subject>Podocytes - metabolism</subject><subject>Podocytes - physiology</subject><subject>Protein kinase C</subject><subject>Protein Kinase C-alpha - genetics</subject><subject>Protein Kinase C-alpha - metabolism</subject><subject>Proteins</subject><subject>Proteinuria</subject><subject>Rodents</subject><subject>Urine</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk0tv1DAQxyMEoqXwDRBEQgJx2MWPOE4uSNWKx4pKrXgdsSbOZONVYm_jBNFvj7ObVhvUA_bB9vg3f3vGnih6TsmScknfbd3QWWiWO2dxSQglNBMPolOac7ZIGeEPj-Yn0RPvt4QInqXp4-iEkYTmlLPT6NeVK52-6Y2Or76sFtDsaoiNjzvcDA30WMbGxu3QGYsx2DKuhxZsXBoosEe_N7UYluPC4q4OYIx2L-m88U-jRxU0Hp9N41n04-OH76vPi4vLT-vV-cVCSyH7BctK0JxgjiXyrEoTnnBeMJIWrBKVLKRIU9CE5RXogmiaAS11CCUrMkCJwM-ilwfdXeO8mlLjFWVZngiesCwQ6wNROtiqXWda6G6UA6P2BtdtFHQhDQ0qERqKXOuS0kRSCZwxAgWvUi4EL_Kg9X46bShC9Bpt30EzE53vWFOrjfutWCaEJONl3kwCnbse0PeqNV5j04BFN3glOc9pwlIRyFf_kPcHN1EbCPc3tnLhWD1qqvNE8iyXUqaBWt5DhV5ia3T4RpUJ9pnD25lDYHr8029g8F6tv339f_by55x9fcTWCE1fe9cMvXHWz8HkAOrOed9hdZdjStRYBbfZUGMVqKkKgtuL4_e5c7r99vwvwwgCNQ</recordid><startdate>20100416</startdate><enddate>20100416</enddate><creator>Tossidou, Irini</creator><creator>Teng, Beina</creator><creator>Menne, Jan</creator><creator>Shushakova, Nelli</creator><creator>Park, Joon-Keun</creator><creator>Becker, Jan U</creator><creator>Modde, Friedrich</creator><creator>Leitges, Michael</creator><creator>Haller, Hermann</creator><creator>Schiffer, Mario</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20100416</creationdate><title>Podocytic PKC-alpha is regulated in murine and human diabetes and mediates nephrin endocytosis</title><author>Tossidou, Irini ; Teng, Beina ; Menne, Jan ; Shushakova, Nelli ; Park, Joon-Keun ; Becker, Jan U ; Modde, Friedrich ; Leitges, Michael ; Haller, Hermann ; Schiffer, Mario</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-28dac30e9ede38f643433b206b2f5f7b7566ac029facb0c18a1dc8668b8ae7ea3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Activation</topic><topic>Analysis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Biopsy</topic><topic>Biotechnology</topic><topic>Data analysis</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus - 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Academic</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>Tossidou, Irini</au><au>Teng, Beina</au><au>Menne, Jan</au><au>Shushakova, Nelli</au><au>Park, Joon-Keun</au><au>Becker, Jan U</au><au>Modde, Friedrich</au><au>Leitges, Michael</au><au>Haller, Hermann</au><au>Schiffer, Mario</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Podocytic PKC-alpha is regulated in murine and human diabetes and mediates nephrin endocytosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2010-04-16</date><risdate>2010</risdate><volume>5</volume><issue>4</issue><spage>e10185</spage><epage>e10185</epage><pages>e10185-e10185</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Microalbuminuria is an early lesion during the development of diabetic nephropathy. The loss of high molecular weight proteins in the urine is usually associated with decreased expression of slit diaphragm proteins. Nephrin, is the major component of the glomerular slit diaphragm and loss of nephrin has been well described in rodent models of experimental diabetes as well as in human diabetic nephropathy.
In this manuscript we analyzed the role of PKC-alpha (PKCalpha) on endocytosis of nephrin in podocytes. We found that treatment of diabetic mice with a PKCalpha-inhibitor (GO6976) leads to preserved nephrin expression and reduced proteinuria. In vitro, we found that high glucose stimulation would induce PKCalpha protein expression in murine and human podocytes. We can demonstrate that PKCalpha mediates nephrin endocytosis in podocytes and that overexpression of PKCalpha leads to an augmented endocytosis response. After PKC-activation, we demonstrate an inducible association of PKCalpha, PICK1 and nephrin in podocytes. Moreover, we can demonstrate a strong induction of PKCalpha in podocytes of patients with diabetic nephropathy.
We therefore conclude that activation of PKCalpha is a pathomechanistic key event during the development of diabetic nephropathy. PKCalpha is involved in reduction of nephrin surface expression and therefore PKCalpha inhibition might be a novel target molecule for anti-proteinuric therapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20419132</pmid><doi>10.1371/journal.pone.0010185</doi><tpages>e10185</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Activation Analysis Animal models Animals Biopsy Biotechnology Data analysis Diabetes Diabetes mellitus Diabetes Mellitus - enzymology Diabetes Mellitus - metabolism Diabetic nephropathies Diabetic Nephropathies - etiology Diabetic Nephropathies - pathology Diabetic nephropathy Diaphragm (anatomy) Endocytosis Gene Expression Regulation, Enzymologic Glucose Glucose - pharmacology Humans Kinases Laboratories Ligands Mediation Medical schools Medicine Membrane Proteins - metabolism Mice Molecular weight Nephrology Nephrology/Chronic Kidney Disease Nephrology/Renal Physiology Nephropathy Pathology Podocytes - metabolism Podocytes - physiology Protein kinase C Protein Kinase C-alpha - genetics Protein Kinase C-alpha - metabolism Proteins Proteinuria Rodents Urine |
| title | Podocytic PKC-alpha is regulated in murine and human diabetes and mediates nephrin endocytosis |
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