S100B is required for high glucose-induced pro-fibrotic gene expression and hypertrophy in mesangial cells

Abstract

The advanced glycation end‑product (AGE)‑receptor for AGE (RAGE) axis induces transforming growth factor‑β (TGF‑β) expression, cell hypertrophy and increases extracellular matrices that are indicated in the pathogenesis of diabetic nephropathy (DN). RAGE binds to numerous ligands besides AGE, including S100B. In the present study, the roles of S100B in high glucose‑induced p21WAF1, extracellular matrices, TGF‑βl and cell hypertrophy in mouse mesangial (MES13) cells were investigated. High glucose (30 mM) time‑dependently (24‑72 h) induced S100B expression. High glucose and exogenous S100B (1 µM) time‑dependently increased p21WAF1 gene transcription and protein expression, increased type IV collagen and fibronectin protein expression, and TGF‑β gene transcription and bioactivity. Exogenous S100B also time‑dependently activated the extracellular regulated kinases (ERK1/2), p38 kinase and c‑Jun N‑terminal kinase (JNK) signaling pathways. Exogenous S100B‑induced TGF‑β gene transcription and bioactivity were attenuated by SB203580 (p38 kinase inhibitor) and PD98059 (ERK1/2 inhibitor). Finally, the knockdown of S100B by small interfering RNA (siRNA) attenuated high glucose‑induced TGF‑β gene transcription and bioactivity, type IV collagen and fibronectin protein expression and p21WAF1 protein expression. Thus, S100B induced TGF‑β via the ERK1/2 and p38 kinase pathways in mesangial cells. Additionally, high glucose‑induced pro‑fibrotic genes (TGF‑β, type IV collagen and fibronectin) and cell hypertrophy‑related p21WAF1 are dependent on S100B.

Transforming Growth Factor-Beta1 in Diabetic Kidney Disease

“…Angiotensin-II, which was elevated in mesangial cells and glomerular endothelial cells, has been implicated in activating TGF-β1 by generation of ROS from nicotinamide adenine dinucleotide phosphate oxidases (Lee, 2011;Morales et al, 2012) or by activating protein kinase C-and p38 MAPK-dependent pathways (Weigert et al, 2002). Hyperglycemia, mechanical stretch, and advanced glycation end products were found to upregulate TGF-β1 in DKD (Gruden et al, 2000;Chuang et al, 2015). TSP-1, a prototypic matricellular ECM protein, was heavily deposited in glomeruli of patients with DKD (Hohenstein et al, 2008).…”

Sitagliptin's renoprotective effect in a diabetic nephropathy model in rats: The potential role of PI3K/AKT pathway

“…Furthermore, hyperglycemia, ROS, proinflammatory cytokines, and advanced glycation end products were found to upregulate TGF-β1 expression in DKD [55,56]. TGF-β1 regulated fibrosis in DKD through F I G U R E 9 Avidin-biotin peroxidase for α-SMA X400: (a) control group, (b) diabetic group, and (c) treated group.…”

Ubiquitination and deubiquitination emerge as players in idiopathic pulmonary fibrosis pathogenesis and treatment

“…NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with IPF (49), and NOX4 regulates TGF-β1-induced fibroblast differentiation by modulating activation of SMAD2/3 (49). Recently, Tsubouchi et al demonstrated that azithromycin (AZM) increases NOX4 degradation in the proteasome and exhibits an antifibrotic effect in bleomycin-injured mice (50). Interestingly, AZM increased STUB1 protein levels and proteasome activity, and AZM-mediated NOX4 degradation was dependent on STUB1 (50), indicating an antifibrotic effect of STUB1.…”