Hyperglycemia Causes Renal Cell Damage via CCN2-Induced Activation of the TrkA Receptor
Implications for Diabetic Nephropathy
- Maria Fragiadaki1⇓,
- Nicola Hill1,
- Reiko Hewitt1,
- George Bou-Gharios1,2,
- Terence Cook1,3,
- Frederick W. Tam1,
- Jan Domin1,4 and
- Roger M. Mason1⇓
- 1Renal Section, Hammersmith Campus, Division of Inflammation and Immunology, Imperial College London, London, U.K.
- 2Kennedy Institute of Rheumatology, Imperial College London, London, U.K.
- 3Histopathology, Imperial College London, London, U.K.
- 4Division of Sciences, University of Bedfordshire, Luton, U.K.
- Corresponding authors: Roger M. Mason, , and Maria Fragiadaki, or .
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.
- Received August 16, 2011.
- Accepted March 19, 2012.
- © 2012 by the American Diabetes Association.
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