| Evaluation of JNK blockade as an early intervention treatment for type 1 diabetic nephropathy in hypertensive rats. | |
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MedLine Citation:
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PMID: 21876346 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND/AIMS: The c-Jun amino-terminal kinase (JNK) signaling pathway is activated in human kidney diseases and promotes renal injury in experimental glomerulonephritis. In this study, we examined whether JNK signaling plays a role in the development of diabetic nephropathy or in regulating hypertension, which exacerbates diabetic renal injury. METHODS: Diabetes was induced in spontaneously hypertensive rats (SHR) using streptozotocin. At week 16 of diabetes, rats with equivalent hyperglycemia and albuminuria were randomized into groups which received no treatment, vehicle alone or a selective JNK inhibitor (CC-930, 60 mg/kg/bid) for 10 weeks. These rats were assessed for hypertension and progression of renal damage. RESULTS: At week 16, diabetic rats showed increased kidney JNK activation compared with nondiabetic controls. Effective JNK inhibition was demonstrated at week 26 by reductions in c-Jun phosphorylation. CC-930 did not affect blood pressure, kidney hypertrophy, glomerular hyperfiltration, podocyte loss, glomerular fibrosis or tubulointerstitial injury in diabetic SHR. However, CC-930 reduced macrophages and ccl2 mRNA levels in diabetic kidneys. In contrast, CC-930 exacerbated albuminuria at week 26, which was associated with reduced glomerular mRNA levels of the podocyte-specific molecules, nephrin and podocin. CONCLUSION: JNK inhibition does not prevent the progression of early diabetic renal injury in hypertensive rats, which contrasts with the ability of JNK inhibition to suppress albuminuria and injury in experimental glomerulonephritis. |
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Authors:
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Andy K H Lim; Frank Y Ma; David J Nikolic-Paterson; Elyce Ozols; Morag J Young; Brydon L Bennett; Glenn C Friedman; Gregory H Tesch |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-08-26 |
Journal Detail:
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Title: American journal of nephrology Volume: 34 ISSN: 1421-9670 ISO Abbreviation: Am. J. Nephrol. Publication Date: 2011 |
Date Detail:
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Created Date: 2011-10-25 Completed Date: 2012-03-20 Revised Date: 2012-04-05 |
Medline Journal Info:
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Nlm Unique ID: 8109361 Medline TA: Am J Nephrol Country: Switzerland |
Other Details:
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Languages: eng Pagination: 337-46 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 S. Karger AG, Basel. |
Affiliation:
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Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Albuminuria
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chemically induced Animals Blood Pressure Body Weight Cyclohexanols / pharmacology* Diabetes Mellitus, Experimental / drug therapy Diabetes Mellitus, Type 1 / drug therapy, pathology* Diabetic Nephropathies / drug therapy, pathology* Early Medical Intervention Hypertension / complications, pathology Hypertrophy Immunohistochemistry / methods Inhibitory Concentration 50 MAP Kinase Kinase 4 / antagonists & inhibitors* Male Protein Kinase Inhibitors / pharmacology* Purines / pharmacology* Rats Rats, Inbred SHR Real-Time Polymerase Chain Reaction |
| Chemical | |
Reg. No./Substance:
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0/4-(9-(tetrahydrofuran-3-yl))-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylaminocyclohexan-1-ol; 0/Cyclohexanols; 0/Protein Kinase Inhibitors; 0/Purines; EC 2.7.12.2/MAP Kinase Kinase 4 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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