title: 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.
abstract: 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.
authors.affiliation: Department of Medicine and the Vascular Biology Center, Georgia Health Sciences University, 1459 Laney-Walker Blvd, Augusta, GA 30912, USA.
authors.forename: Riyaz
authors.initials: R
authors.lastname: Mohamed
authors.forename: Calpurnia
authors.initials: C
authors.lastname: Jayakumar
authors.forename: Punithavathi V
authors.initials: PV
authors.lastname: Ranganathan
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
mesh_terms: D000419:Albuminuria / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002645:Chickens; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D015232:Dinoprostone / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D009414:Nerve Growth Factors / Q000097:blood / Q000378:metabolism*; D000075388:Netrin-1; D009928:Organ Specificity / Q000187:drug effects; D019076:Transgenes / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000097:blood / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D005947:Glucose; D015232:Dinoprostone