Acute knockdown of uncoupling protein-2 increases uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys
Increased O(2) metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O(2) consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis tha...
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| Veröffentlicht in: | PloS one 2012-07, Vol.7 (7), p.e39635-e39635 |
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| creator | Friederich-Persson, Malou Aslam, Shakil Nordquist, Lina Welch, William J Wilcox, Christopher S Palm, Fredrik |
| description | Increased O(2) metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O(2) consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (-30-50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT. |
| doi_str_mv | 10.1371/journal.pone.0039635 |
| format | Article |
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Mitochondrial uncoupling increases O(2) consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (-30-50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0039635</identifier><identifier>PMID: 22768304</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenine ; Adenosine diphosphate ; Adenosine Diphosphate - genetics ; Adenosine Diphosphate - metabolism ; Adenosine monophosphate ; Animals ; Binding sites ; Biology ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - genetics ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Experimental - pathology ; Diabetic Nephropathies - genetics ; Diabetic Nephropathies - metabolism ; Diabetic Nephropathies - pathology ; Gene Knockdown Techniques ; Glucose ; Guanosine Diphosphate - genetics ; Guanosine Diphosphate - metabolism ; Hypertension ; Hypoxia ; Ion Channels - genetics ; Ion Channels - metabolism ; Kidney Cortex - metabolism ; Kidney Cortex - pathology ; Kidney diseases ; Kidneys ; Male ; Malondialdehyde ; Malondialdehyde - metabolism ; Medicine ; Membrane potential ; Membrane Potential, Mitochondrial - genetics ; Metabolism ; Mitochondria ; Mitochondria - genetics ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondrial ADP, ATP Translocases - genetics ; Mitochondrial ADP, ATP Translocases - metabolism ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - metabolism ; Mitochondrial uncoupling protein 2 ; Musculoskeletal system ; Nephrology ; Oxidative Stress ; Oxygen - metabolism ; Phosphorylation ; Physiological aspects ; Physiology ; Protein expression ; Proteins ; Purines ; Rats ; Rats, Sprague-Dawley ; Renal cortex ; Respiration ; Rodents ; siRNA ; Statistics ; Streptozocin ; Uncoupling Protein 2</subject><ispartof>PloS one, 2012-07, Vol.7 (7), p.e39635-e39635</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Friederich Persson 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. 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Mitochondrial uncoupling increases O(2) consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (-30-50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.</description><subject>Adenine</subject><subject>Adenosine diphosphate</subject><subject>Adenosine Diphosphate - genetics</subject><subject>Adenosine Diphosphate - metabolism</subject><subject>Adenosine monophosphate</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Biology</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - genetics</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetic Nephropathies - genetics</subject><subject>Diabetic Nephropathies - metabolism</subject><subject>Diabetic Nephropathies - pathology</subject><subject>Gene Knockdown Techniques</subject><subject>Glucose</subject><subject>Guanosine Diphosphate - genetics</subject><subject>Guanosine Diphosphate - metabolism</subject><subject>Hypertension</subject><subject>Hypoxia</subject><subject>Ion Channels - genetics</subject><subject>Ion Channels - metabolism</subject><subject>Kidney Cortex - metabolism</subject><subject>Kidney Cortex - pathology</subject><subject>Kidney diseases</subject><subject>Kidneys</subject><subject>Male</subject><subject>Malondialdehyde</subject><subject>Malondialdehyde - metabolism</subject><subject>Medicine</subject><subject>Membrane potential</subject><subject>Membrane Potential, Mitochondrial - genetics</subject><subject>Metabolism</subject><subject>Mitochondria</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Mitochondrial ADP, ATP Translocases - genetics</subject><subject>Mitochondrial ADP, ATP Translocases - metabolism</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>Mitochondrial uncoupling protein 2</subject><subject>Musculoskeletal system</subject><subject>Nephrology</subject><subject>Oxidative Stress</subject><subject>Oxygen - metabolism</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Physiology</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Purines</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Renal cortex</subject><subject>Respiration</subject><subject>Rodents</subject><subject>siRNA</subject><subject>Statistics</subject><subject>Streptozocin</subject><subject>Uncoupling Protein 2</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tq3DAURU1padK0f1BaQaG00JlKlmzLL4UhvQUCgV7yKmTpeEaJR3IlOZcf6fdWzkzCuARa9GAhrb11vKWTZc8JnhNakfdnbvBWdvPeWZhjTOuSFg-yfVLTfFbmmD7cme9lT0I4w7igvCwfZ3t5XpWcYraf_V6oIQI6t06da3dpkWvRYJUb-s7YJeq9i2DsLEfGKg8yQNjdvjASxRUgqcEaC8gOqgMXjQYUvbShdz6CR9JqpOFW766MltFcAArRQwjJGmkjG4hGoXOjLVyHp9mjVnYBnm2_B9nPz59-HH6dHZ98OTpcHM8Uz3mc8brluqQt48AZq1VdlAQzXGqacyiKNuctblgBNG_qthpnXFKSopK0gSbFcZC93Pj2nQtiG2kQhOYFzqsas0QcbQjt5JnovVlLfy2cNOJmwfmlkD5V3oEAxtsKV6ApKZhiNR-rAEIbybhmDU5e7zZe4RL6oZm4fTSnixu3zgyiqmkxHv1hW9zQrEErsCnUbqKa7lizEkt3ISjlnODxvDdbA-9-DRCiWJugoOukBTeMv8k44yRn9N8ozhmuS1bXCX31F3p_bltqKVM0xrYulahGU7FgVUUI4_WY__weKg0Na6PSy25NWp8I3k4EiYlwFZdyCEEcff_2_-zJ6ZR9vcOuQHZxFVw3RONsmIJsAyrvQvDQ3t0HwWJszNs0xNiYYtuYSfZi9y7vRLedSP8Aybs1Pw</recordid><startdate>20120702</startdate><enddate>20120702</enddate><creator>Friederich-Persson, Malou</creator><creator>Aslam, Shakil</creator><creator>Nordquist, Lina</creator><creator>Welch, William J</creator><creator>Wilcox, Christopher S</creator><creator>Palm, Fredrik</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>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>ABXSW</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>DG8</scope><scope>ZZAVC</scope><scope>DOA</scope></search><sort><creationdate>20120702</creationdate><title>Acute knockdown of uncoupling protein-2 increases uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys</title><author>Friederich-Persson, Malou ; Aslam, Shakil ; Nordquist, Lina ; Welch, William J ; Wilcox, Christopher S ; Palm, Fredrik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c828t-89f8d63f48e8449c95610406d328e55f28f0b45e32b9f7b45e8a31396a3beb053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenine</topic><topic>Adenosine diphosphate</topic><topic>Adenosine Diphosphate - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SWEPUB Linköpings universitet full text</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Linköpings universitet</collection><collection>SwePub Articles full text</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>Friederich-Persson, Malou</au><au>Aslam, Shakil</au><au>Nordquist, Lina</au><au>Welch, William J</au><au>Wilcox, Christopher S</au><au>Palm, Fredrik</au><au>Chan, Sherine Swee Lin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acute knockdown of uncoupling protein-2 increases uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-07-02</date><risdate>2012</risdate><volume>7</volume><issue>7</issue><spage>e39635</spage><epage>e39635</epage><pages>e39635-e39635</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Increased O(2) metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O(2) consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (-30-50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22768304</pmid><doi>10.1371/journal.pone.0039635</doi><tpages>e39635</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-07, Vol.7 (7), p.e39635-e39635 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1325027904 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SWEPUB Freely available online; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenine Adenosine diphosphate Adenosine Diphosphate - genetics Adenosine Diphosphate - metabolism Adenosine monophosphate Animals Binding sites Biology Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Experimental - pathology Diabetic Nephropathies - genetics Diabetic Nephropathies - metabolism Diabetic Nephropathies - pathology Gene Knockdown Techniques Glucose Guanosine Diphosphate - genetics Guanosine Diphosphate - metabolism Hypertension Hypoxia Ion Channels - genetics Ion Channels - metabolism Kidney Cortex - metabolism Kidney Cortex - pathology Kidney diseases Kidneys Male Malondialdehyde Malondialdehyde - metabolism Medicine Membrane potential Membrane Potential, Mitochondrial - genetics Metabolism Mitochondria Mitochondria - genetics Mitochondria - metabolism Mitochondria - pathology Mitochondrial ADP, ATP Translocases - genetics Mitochondrial ADP, ATP Translocases - metabolism Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Mitochondrial uncoupling protein 2 Musculoskeletal system Nephrology Oxidative Stress Oxygen - metabolism Phosphorylation Physiological aspects Physiology Protein expression Proteins Purines Rats Rats, Sprague-Dawley Renal cortex Respiration Rodents siRNA Statistics Streptozocin Uncoupling Protein 2 |
| title | Acute knockdown of uncoupling protein-2 increases uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys |
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