Document Detail

Kidney proximal tubular epithelial-specific overexpression of netrin-1 suppresses inflammation and albuminuria through suppression of COX-2-mediated PGE2 production in streptozotocin-induced diabetic mice.
MedLine Citation:
PMID:  23041393     Owner:  NLM     Status:  MEDLINE    
Inflammation plays a key role in the development and progression of diabetic kidney disease; however, the role of the anti-inflammatory molecule netrin-1 in diabetic kidney disease is unknown. We examined the role of netrin-1 in diabetes-induced kidney inflammation and injury using tubule-specific netrin-1 transgenic mice. Diabetes was induced using streptozotocin in wild-type and netrin-1 transgenic animals. Kidney function, fibrosis, glucose excretion, albuminuria, and inflammation were evaluated. The mechanism of netrin-1-induced suppression of inflammation was studied in vitro using a proximal tubular epithelial cell line. Diabetes was associated with increased infiltration of neutrophils and macrophages, chemokine expression, and tubular epithelial cell apoptosis in kidney. These changes were minimal in kidney of netrin-1 transgenic mice. In addition, diabetes induced a large increase in the excretion of prostaglandin E2 (PGE2) in urine, which was suppressed in netrin-1 transgenic mice. Netrin-1-induced suppression of PGE2 production was mediated through suppression of NFκB-mediated cyclooxygenase-2 (COX-2) in renal tubular epithelial cells. Furthermore, netrin-1 also increased albumin uptake by proximal tubular epithelial cells through the PI3K and ERK pathways without increasing glucose uptake. These findings suggest that netrin-1 is a major regulator of inflammation and apoptosis in diabetic nephropathy and may be a useful therapeutic molecule for treating chronic kidney diseases such as diabetic nephropathy.
Riyaz Mohamed; Calpurnia Jayakumar; Punithavathi V Ranganathan; Vadivel Ganapathy; Ganesan Ramesh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-02
Journal Detail:
Title:  The American journal of pathology     Volume:  181     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-05-01     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1991-2002     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Albuminuria / blood,  complications,  enzymology,  pathology*
Apoptosis / drug effects
Cell Movement / drug effects
Cyclooxygenase 2 / metabolism*
Cytokines / secretion
Diabetes Mellitus, Experimental / blood,  complications,  enzymology,  pathology*
Dinoprostone / biosynthesis*
Epithelial Cells / drug effects,  enzymology,  pathology
Gene Expression / drug effects
Glucose / pharmacology
Hyperglycemia / blood,  complications,  enzymology,  pathology
Inflammation / blood,  complications,  enzymology,  pathology*
Kidney Tubules, Proximal / drug effects,  enzymology,  pathology*
Leukocytes / drug effects,  pathology
Mesangial Cells / drug effects,  metabolism,  pathology
Mice, Transgenic
NF-kappa B / metabolism
Nerve Growth Factors / blood,  metabolism*
Organ Specificity / drug effects
Transgenes / genetics
Tumor Suppressor Proteins / blood,  metabolism*
Grant Support
1-R01-DK083379-01A3/DK/NIDDK NIH HHS; R01 DK083379/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Cytokines; 0/NF-kappa B; 0/Nerve Growth Factors; 0/Tumor Suppressor Proteins; 158651-98-0/netrin-1; EC 1.14.99.-/Ptgs2 protein, mouse; EC 2; IY9XDZ35W2/Glucose; K7Q1JQR04M/Dinoprostone
Comment In:
Nat Rev Nephrol. 2012 Dec;8(12):681   [PMID:  23090448 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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