Hyperglycemia Causes Renal Cell Damage via CCN2-Induced Activation of the TrkA Receptor

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.

Neurotrophins and Neurotrophin Receptors in Proliferative Diabetic Retinopathy

“…In vivo studies demonstrated immunoreactivity for NT-3 and Trk receptors in vessel walls, and stromal fibroblasts of lung cancer specimens [11]. In addition, TrkA expression and activation are increased in the kidneys from patients with diabetic nephropathy [31], and TrkA and TrkC expression is increased in human diabetic skin [32]. Our Western blot analysis demonstrated the presence of intact and cleaved TrkA and TrkB in the vitreous from PDR patients.…”

Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions

“…The involvement of CCN2 in this phase is well represented by the fact that CCN2 regulates the behaviour of the mediators of inflammation and vice versa. Integrin αvβ5, TrkA and epidermal growth factor receptor (EGFR) on the cell surface were shown to mediate inflammatory response and tissue damage induced by CCN2 [11,68,73,74]. In fact, elevated CCN2 expression is observed in inflamed joints of patients with rheumatoid arthritis and osteoarthritis [59,71].…”

Yin and Yang revisited: CCN3 as an anti-fibrotic therapeutic?

“…Indeed, CCN2 is a wellestablished downstrem mediator of fibrosis (Abdel Wahab and Mason 2004;Phanish et al 2010;Fragiadaki et al 2012;Liu et al 2013). However, issues of possible functional redundancy among CCN family members exist; for example, both CCN4 and CCN6 have been proposed to be potent fibrogenic mediators (Königshoff et al 2009;Jian et al 2014;Batmunkh et al 2011).…”