Gremlin Regulates Tubular Epithelial to Mesenchymal Transition via VEGFR2: Potential Role in Renal Fibrosis

Abstract

Chronic kidney disease (CKD) is emerging as an important health problem due to the increase number of CKD patients and the absence of an effective curative treatment. Gremlin has been proposed as a novel therapeutic target for renal inflammatory diseases, acting via Vascular Endothelial Growth Factor Receptor-2 (VEGFR2). Although many evidences suggest that Gremlin could regulate renal fibrosis, the receptor involved has not been yet clarified. Gremlin, as other TGF-β superfamily members, regulates tubular epithelial to mesenchymal transition (EMT) and, therefore, could contribute to renal fibrosis. In cultured tubular epithelial cells Gremlin binding to VEGFR2 is linked to proinflammatory responses. Now, we have found out that in these cells VEGFR2 is also involved in the profibrotic actions of Gremlin. VEGFR2 blockade by a pharmacological kinase inhibitor or gene silencing diminished Gremlin-mediated gene upregulation of profibrotic factors and restored changes in EMT-related genes. Moreover, VEGFR2 inhibition blocked EMT phenotypic changes and dampened the rate of wound healing in response to Gremlin. The role of VEGFR2 in experimental fibrosis was evaluated in experimental unilateral ureteral obstruction. VEFGR2 inhibition diminished the upregulation of profibrotic genes and EMT changes, as well as the accumulation of extracellular matrix proteins, such as fibronectin and collagens in the obstructed kidneys. Notch pathway activation participates in renal damage progression by regulating cell growth/proliferation, regeneration and inflammation. In cultured tubular epithelial cells, Notch inhibition markedly downregulated Gremlin-induced EMT changes and wound healing speed. These results show that Gremlin regulates the EMT process via VEGFR2 and Notch pathway activation, suggesting that the Gremlin/VEGFR2 axis could be a potential therapeutic target for CKD.

DHA inhibits Gremlin-1-induced epithelial-to-mesenchymal transition via ERK suppression in human breast cancer cells

“…The GREM1-VEGFR2 pathway is involved in renal inflammation [52] and the proliferation of retinal pigmentation epithelial cells [48]. In addition, GREM1 induces EMT via VEGFR2 activation in tubular epithelial cells [36]. Little is known about the binding between GREM1 and receptors, but further studies on the direct binding of GREM1 to specific receptors are needed to elucidate the mechanism of EMT induction.…”

“…GREM1 is also involved in the fibrosis of various organs, including lung [29][30][31], kidney [32][33][34], and pancreas [35]. Interestingly, EMT phenomenon induced by GREM1 is known to be important for organ fibrosis [36] and tumor promotion [37,38]. GREM1 activates EMT process and profibrotic phenotype in tubular epithelial cells [36].…”

“…Interestingly, EMT phenomenon induced by GREM1 is known to be important for organ fibrosis [36] and tumor promotion [37,38]. GREM1 activates EMT process and profibrotic phenotype in tubular epithelial cells [36]. It has been reported that mesenchymal stromal cell-derived GREM1 can promote EMT in human esophageal squamous cell carcinoma [37].…”

Advances in Understanding the Effects of Erythropoietin on Renal Fibrosis

“…The EMT is pathologically reactivated in, and contributes to, the progression of fibrosis (56). Tubulointerstitial fibroblasts, derived from tubular epithelial cells during the EMT, are among the most important effector cells facilitating the progression of renal fibrosis (57,58). In the past few decades, many studies have examined the role of the EMT during organ fibrosis, wound healing, and cancer metastasis.…”

No evidence of Gremlin1-mediated activation of VEGFR2 signaling in endothelial cells

“…This group also published several follow-up reports on the requirement of αvβ3 integrins for GREM1-mediated VEGFR2 activation (28) and the ability of monomeric GREM1 to act as an antagonist of VEGFR2 (29). Sporadic reports in the literature have suggested similar GREM1VEGFR2 signalling in ARPE-19 retinal cells (30), HK-2 kidney tubule epithelial cells (31,32), HaCaT skin keratinocytes and primary skin fibroblasts (33). In contrast, a recent paper suggests that GREM1 blocks VEGF signalling in the pulmonary microvascular endothelium (34).…”