Hyperglycemia Causes Renal Cell Damage via CCN2-Induced Activation of the TrkA Receptor: Implications for Diabetic Nephropathy
Author(s)
Type
Journal Article
Abstract
CCN2, a secreted profibrotic protein, is highly expressed in diabetic nephropathy (DN) and implicated in its pathogenesis; however, the actions of CCN2 in DN remain elusive. We previously demonstrated that CCN2 triggers signaling via tropomyosin receptor kinase A (TrkA). Trace expression of TrkA is found in normal kidneys, but its expression is elevated in several nephropathies; yet its role in DN is unexplored. In this study we show de novo expression of TrkA in human and murine DN. We go on to study the molecular mechanisms leading to TrkA activation and show that it involves hypoxia, as demonstrated by ischemia–reperfusion injury and in vitro experiments mimicking hypoxia, implicating hypoxia as a common pathway leading to disease. We also expose renal cells to hyperglycemia, which led to TrkA phosphorylation in mesangial cells, tubular epithelial cells, and podocytes but not in glomerular endothelial cells and renal fibroblasts. In addition, we report that hyperglycemia caused an induction of phosphorylated extracellular signal–related kinase 1/2 and Snail1 that was abrogated by silencing of TrkA or CCN2 using small interfering RNA. In conclusion, we provide novel evidence that TrkA is activated in diabetic kidneys and suggest that anti-TrkA therapy may prove beneficial in DN.
Date Issued
2012-09-01
Date Acceptance
2012-03-19
Citation
Diabetes, 2012, 61 (9), pp.2280-2288
ISSN
0012-1797
Publisher
AMER DIABETES ASSOC
Start Page
2280
End Page
2288
Journal / Book Title
Diabetes
Volume
61
Issue
9
Copyright Statement
© 2012 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. See http://creativecommons.org/licenses/by
-nc-nd/3.0/ for details.
long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. See http://creativecommons.org/licenses/by
-nc-nd/3.0/ for details.
Sponsor
Medical Research Council (MRC)
Grant Number
G0500936
Subjects
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
ENDOCRINOLOGY & METABOLISM
TISSUE GROWTH-FACTOR
HUMAN MESANGIAL CELLS
HIGH GLUCOSE
GENE-EXPRESSION
FACTOR-BETA
IN-VIVO
FIBROSIS
HYPOXIA
KIDNEY
MICE
Publication Status
Published