Bradykinin inhibits high glucose- and growth factor-induced collagen synthesis in mesangial cells through the B2-kinin receptor

Abstract

Mesangial matrix expansion is an early lesion leading to glomeruloclerosis and chronic renal diseases. A beneficial effect is achieved with angiotensin I-converting enzyme inhibitors (ACEI), which also favor bradykinin (BK) B2 receptor (B2R) activation. To define the underlying mechanism, we hypothesized that B2R activation could be a negative regulator of collagen synthesis in mesangial cells (MC). We investigated the effect of BK on collagen synthesis and signaling in MC. Inflammation was evaluated by intercellular adhesion molecule-1 (ICAM-1) expression. BK inhibited collagen I and IV synthesis stimulated by high glucose, epithelial growth factor (EGF), and transforming growth factor-β (TGF-β) but did not alter ICAM-1. Inhibition of collagen synthesis was B2R but not B1R mediated. PKC or phosphatidylinositol 3-kinase (PI3K) inhibitors mimicked the BK effect. B2R activation inhibited TGF-β- and EGF-induced Erk1/2, Smad2/3, Akt S473, and EGFR phosphorylation. A phosphatase inhibitor prevented BK effects. The in vivo impact of B2R on mesangial matrix expansion was assessed in streptozotocin-diabetic rodents. Deletion of B2R increased mesangial matrix expansion and albuminuria in diabetic mice. In diabetic rats, matrix expansion and albuminuria were prevented by ACEI but not by ACEI and B2R antagonist cotreatment. Consistently, the lowered BK content of diabetic glomeruli was restored by ACEI. In conclusion, deficient B2R activation aggravated mesangial matrix expansion in diabetic rodents whereas B2R activation reduced MC collagen synthesis by a mechanism targeting Erk1/2 and Akt, common pathways activated by EGF and TGF-β. Taken together, the data support the hypothesis of an antifibrosing effect of B2R activation.

Store–Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression

“…5,[34][35][36][37][38] 5,9,[44][45][46][47] We examined if activation of SOC could inhibit high glucose-induced fibrotic response. As shown in Figure 4, high glucose treatment significantly increased expression levels of both fibronectin and Col IV proteins.…”

Effect of bradykinin on renal mesangial cell proliferation and extracellular matrix secretion

“…These effects were independent of the effect of blood pressure lowering caused by the system, particularly in the case of diabetic nephropathy (Kakoki et al, 2004; ., 2007;Pawluczyk et al, 2006Pawluczyk et al, , 2008. BK is the effector peptide of KKS, and in vitro experiments have also confirmed that BK could inhibit MCP induced by FCS, growth factors, and high glucose (Alric et al, 2000;Blaes et al, 2012), as well as arterial smooth muscle cell proliferation that is induced by PDGF-AB. Several in-depth studies have recently emerged to further elucidate the mechanism of the above effects produced by the KKS, especially BK.…”

“…However, BK also played an inhibitory role in proliferation when cells were pre-stimulated with PDGF, as well as on PDGF-induced ERK phosphorylation. Blaes et al (2012) also found that BK could inhibit the synthesis of mesangial cell Col I and Col IV that was induced by high-sugar, epithelial growth factor, and transforming growth factor-b. BK receptors are divided into two main categories, B1 and B2, with its main functions achieved through the B2 receptor (Kakoki et al, 2004;Tan et al, 2004;Abadir et al, 2006;Duka et al, 2006).…”

Effect of bradykinin on TGF-β1-induced retinal pigment epithelial cell proliferation and extracellular matrix secretion

“…Previous studies have shown that BK increases vascular smooth muscle cell proliferation by activating the Erk signaling pathway and that BK may also play a role in collagen synthesis and secretion by inhibiting TGF-β-induced Akt phosphoylation [27]. …”

“…High levels of BK expression have been detected in the serum, vitreous body and retina of PVR rats, which indicates that BK may be associated with PVR development [21]. Nelly Blaes reported that BK inhibits TGF-β-induced collagen production by activating the bradykinin B2 receptor (B2R) [27]. Other studies have found that BK inhibits growth factor-induced cell proliferation and ECM secretion [28].…”