Aldosterone antagonists in monotherapy are protective against streptozotocin-induced diabetic nephropathy in rats
Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiote...
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| creator | Banki, Nora F Ver, Agota Wagner, Laszlo J Vannay, Adam Degrell, Peter Prokai, Agnes Gellai, Renata Lenart, Lilla Szakal, Dorottya-Nagy Kenesei, Eva Rosta, Klara Reusz, Gyorgy Szabo, Attila J Tulassay, Tivadar Baylis, Chris Fekete, Andrea |
| description | Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers. |
| doi_str_mv | 10.1371/journal.pone.0039938 |
| format | Article |
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Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0039938</identifier><identifier>PMID: 22761931</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aldosterone ; Angiotensin ; Angiotensin converting enzyme ; Angiotensin II ; Angiotensins ; Animals ; ATPases ; Biology ; Blood Pressure - drug effects ; Bradycardia ; Cells, Cultured ; Diabetes ; Diabetes mellitus ; Diabetic nephropathies ; Diabetic Nephropathies - prevention & control ; Diabetic nephropathy ; Diet ; Enzyme inhibitors ; Enzymes ; Glucocorticoids ; Glucose ; Heart Rate - drug effects ; Hyperglycemia ; Hyperglycemia - enzymology ; Hypertension ; Kidney diseases ; Kidney Tubules, Proximal - enzymology ; Laboratories ; Lipids ; Localization ; Medicine ; Metabolism ; Mineralocorticoid Receptor Antagonists - pharmacology ; Mineralocorticoid Receptor Antagonists - therapeutic use ; Molecular biology ; Na+/K+-exchanging ATPase ; Nephrology ; Nephropathy ; Pediatrics ; Peptidyl-dipeptidase A ; Prevention ; Professionals ; Public schools ; Rats ; Renal function ; Rodents ; Sodium-Potassium-Exchanging ATPase - metabolism ; Steroids (Organic compounds) ; Streptozocin ; Structure-function relationships ; Studies ; Transcription factors ; Weight control</subject><ispartof>PloS one, 2012-06, Vol.7 (6), p.e39938-e39938</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Banki 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>Banki et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-354cd15cea0ae4b2f1027dd9b650bb7ff7f4fc045c928ff162396cb8429dd6543</citedby><cites>FETCH-LOGICAL-c758t-354cd15cea0ae4b2f1027dd9b650bb7ff7f4fc045c928ff162396cb8429dd6543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386228/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386228/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22761931$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Banki, Nora F</creatorcontrib><creatorcontrib>Ver, Agota</creatorcontrib><creatorcontrib>Wagner, Laszlo J</creatorcontrib><creatorcontrib>Vannay, Adam</creatorcontrib><creatorcontrib>Degrell, Peter</creatorcontrib><creatorcontrib>Prokai, Agnes</creatorcontrib><creatorcontrib>Gellai, Renata</creatorcontrib><creatorcontrib>Lenart, Lilla</creatorcontrib><creatorcontrib>Szakal, Dorottya-Nagy</creatorcontrib><creatorcontrib>Kenesei, Eva</creatorcontrib><creatorcontrib>Rosta, Klara</creatorcontrib><creatorcontrib>Reusz, Gyorgy</creatorcontrib><creatorcontrib>Szabo, Attila J</creatorcontrib><creatorcontrib>Tulassay, Tivadar</creatorcontrib><creatorcontrib>Baylis, Chris</creatorcontrib><creatorcontrib>Fekete, Andrea</creatorcontrib><title>Aldosterone antagonists in monotherapy are protective against streptozotocin-induced diabetic nephropathy in rats</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers.</description><subject>Aldosterone</subject><subject>Angiotensin</subject><subject>Angiotensin converting enzyme</subject><subject>Angiotensin II</subject><subject>Angiotensins</subject><subject>Animals</subject><subject>ATPases</subject><subject>Biology</subject><subject>Blood Pressure - drug effects</subject><subject>Bradycardia</subject><subject>Cells, Cultured</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetic nephropathies</subject><subject>Diabetic Nephropathies - prevention & control</subject><subject>Diabetic nephropathy</subject><subject>Diet</subject><subject>Enzyme inhibitors</subject><subject>Enzymes</subject><subject>Glucocorticoids</subject><subject>Glucose</subject><subject>Heart Rate - drug effects</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - enzymology</subject><subject>Hypertension</subject><subject>Kidney diseases</subject><subject>Kidney Tubules, Proximal - enzymology</subject><subject>Laboratories</subject><subject>Lipids</subject><subject>Localization</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Mineralocorticoid Receptor Antagonists - pharmacology</subject><subject>Mineralocorticoid Receptor Antagonists - therapeutic use</subject><subject>Molecular biology</subject><subject>Na+/K+-exchanging ATPase</subject><subject>Nephrology</subject><subject>Nephropathy</subject><subject>Pediatrics</subject><subject>Peptidyl-dipeptidase A</subject><subject>Prevention</subject><subject>Professionals</subject><subject>Public schools</subject><subject>Rats</subject><subject>Renal function</subject><subject>Rodents</subject><subject>Sodium-Potassium-Exchanging ATPase - metabolism</subject><subject>Steroids (Organic compounds)</subject><subject>Streptozocin</subject><subject>Structure-function 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and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. 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A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22761931</pmid><doi>10.1371/journal.pone.0039938</doi><tpages>e39938</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-06, Vol.7 (6), p.e39938-e39938 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1325034231 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Aldosterone Angiotensin Angiotensin converting enzyme Angiotensin II Angiotensins Animals ATPases Biology Blood Pressure - drug effects Bradycardia Cells, Cultured Diabetes Diabetes mellitus Diabetic nephropathies Diabetic Nephropathies - prevention & control Diabetic nephropathy Diet Enzyme inhibitors Enzymes Glucocorticoids Glucose Heart Rate - drug effects Hyperglycemia Hyperglycemia - enzymology Hypertension Kidney diseases Kidney Tubules, Proximal - enzymology Laboratories Lipids Localization Medicine Metabolism Mineralocorticoid Receptor Antagonists - pharmacology Mineralocorticoid Receptor Antagonists - therapeutic use Molecular biology Na+/K+-exchanging ATPase Nephrology Nephropathy Pediatrics Peptidyl-dipeptidase A Prevention Professionals Public schools Rats Renal function Rodents Sodium-Potassium-Exchanging ATPase - metabolism Steroids (Organic compounds) Streptozocin Structure-function relationships Studies Transcription factors Weight control |
| title | Aldosterone antagonists in monotherapy are protective against streptozotocin-induced diabetic nephropathy in rats |
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