Abstract
Advanced glycation end products (AGE) play a causative role in the development of aberrant phenotypes of intraglomerular mesangial cells, contributing to acute/chronic glomerulonephritis. The aim of this study was to explore mechanistic effects of the flavonoid chrysin present in bee propolis and herbs on actin dynamics, focal adhesion, and the migration of AGE-exposed mesangial cells. The in vitro study cultured human mesangial cells exposed to 33 mM glucose and 100 μg/mL AGE-bovine serum albumin (AGE-BSA) for up to 5 days in the absence and presence of 1–20 μM chrysin. The in vivo study employed db/db mice orally administrated for 10 weeks with 10 mg/kg chrysin. The presence of ≥10 μM chrysin attenuated mesangial F-actin induction and bundle formation enhanced by AGE. Chrysin reduced the mesangial induction of α-smooth muscle actin (α-SMA) by glucose, and diminished the tissue α-SMA level in diabetic kidneys, indicating its blockade of mesangial proliferation. The treatment of chrysin inhibited the activation of vinculin and paxillin and the induction of cortactin, ARP2/3, fascin-1, and Ena/VASP-like protein in AGE-exposed mesangial cells. Oral administration of chrysin diminished tissue levels of cortactin and fascin-1 elevated in diabetic mouse kidneys. Mesangial cell motility was enhanced by AGE, which was markedly attenuated by adding chrysin to cells. On the other hand, chrysin dampened the induction of autophagy-related genes of beclin-1, LC3 I/II, Atg3, and Atg7 in mesangial cells exposed to AGE and in diabetic kidneys. Furthermore, chrysin reduced the mTOR activation in AGE-exposed mesangial cells and diabetic kidneys. The induction of mesangial F-actin, cortactin, and fascin-1 by AGE was deterred by the inhibition of autophagy and mTOR. Thus, chrysin may encumber diabetes-associated formation of actin bundling and focal adhesion and mesangial cell motility through disturbing autophagy and mTOR pathway.
Highlights
Mesangial cells possess irregular structures comprised of flattened cylinder-like cell bodies and contain actin, myosin, and α-actinin at both ends, granting them contractile features [1]
This study investigated the mesangial dynamics of F-actin cytoskeleton and integrin-based focal adhesions in glomerular injury due to glucose and advanced glycation end products (AGE) implicated in the pathogenesis of diabetic complications
The current study examined whether chrysin inhibited glucose- and AGE-stimulated actin cytoskeleton rearrangement and focal adhesion dysfunction in renal mesangial cells
Summary
Mesangial cells possess irregular structures comprised of flattened cylinder-like cell bodies and contain actin, myosin, and α-actinin at both ends, granting them contractile features [1]. The anchoring filaments from mesangial cells to the glomerular basement membrane can influence glomerular capillary blood flow [2,3]. Glomerular mesangial cells migrate in response to platelet-derived growth factor (PDGF). There is emerging evidence for the role of the abnormal migratory polarity of mesangial cells due to glomerular injury in the pathogenesis of proliferative glomerulonephritis [4,7,8]. Glomerular injury-triggered molecular changes in mesangial cells in glomerulonephritis still remain elusive. Directional cell migration entails the establishment of cytoskeletal alterations that are essential for actin polarization and focal adhesion turnover [9,10]. The migratory process is controlled by coordinated actin dynamics and focal adhesion turnover at the peripheral ruffles in migrating mesangial cells [6]. Identifying the key molecular players in motility and clear-cut molecular functions remains challenging
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