| PKC-delta promotes renal tubular cell apoptosis associated with proteinuria. | |
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MedLine Citation:
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PMID: 20395372 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time- and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-delta early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-delta, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-delta blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-delta in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-delta-knockout mice. Taken together, these results suggest that activation of PKC-delta promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases. |
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Authors:
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Xiaoning Li; Navjotsingh Pabla; Qingqing Wei; Guie Dong; Robert O Messing; Cong-Yi Wang; Zheng Dong |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-04-15 |
Journal Detail:
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Title: Journal of the American Society of Nephrology : JASN Volume: 21 ISSN: 1533-3450 ISO Abbreviation: J. Am. Soc. Nephrol. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-01 Completed Date: 2010-07-21 Revised Date: 2011-08-25 |
Medline Journal Info:
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Nlm Unique ID: 9013836 Medline TA: J Am Soc Nephrol Country: United States |
Other Details:
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Languages: eng Pagination: 1115-24 Citation Subset: IM |
Affiliation:
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Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans' Affairs Medical Center, Augusta, Georgia 30912, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetophenones
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pharmacology Albumins / metabolism, pharmacology Animals Apoptosis / drug effects, physiology* Benzopyrans / pharmacology Caspases / metabolism Cell Line Cytochromes c / metabolism Diabetes Mellitus, Experimental / complications Disease Models, Animal Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Kidney Tubules, Proximal / drug effects, pathology, physiopathology* Male Mice Mice, Knockout Protein Kinase C-delta / antagonists & inhibitors, genetics, physiology* Proteinuria / etiology, metabolism, physiopathology* Proto-Oncogene Proteins c-bcl-2 / metabolism Rats Streptozocin bcl-2-Associated X Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Acetophenones; 0/Albumins; 0/Benzopyrans; 0/Enzyme Inhibitors; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2-Associated X Protein; 18883-66-4/Streptozocin; 82-08-6/rottlerin; 9007-43-6/Cytochromes c; EC 2.7.11.13/Protein Kinase C-delta; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
Comment In:
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J Am Soc Nephrol. 2010 Jul;21(7):1063-5
[PMID:
20558537
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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