Fluvastatin attenuated the effect of expression of β1 integrin in PAN-treated podocytes by inhibiting reactive oxygen species

Abstract

It is well accepted that β1 integrin plays a key role in maintaining normal podocytes form and functions; however, its mechanism of the potential protective effect remains unclear. Furthermore, the investigation and understanding of the non-lipid-dependent renal protection of Statins in addition to well-known lipid-lowering effect may provide the therapeutic utility and ultimately improve clinical outcome for patients with renal diseases. In the present study, we investigated the effect and mechanism of fluvastatin (FLV) on the expression of β1 integrin in puromycin aminonucleoside (PAN)-treated podocytes in vitro. Cultured human podocytes were treated with PAN, and/or different concentrations of FLV (1 × 10(-8)-1 × 10(-5 )mol/l), superoxide dismutase (SOD), or H2O2, respectively. The expression of β1 integrin and reactive oxygen species (ROS) in human podocytes under each experimental condition was evaluated by western blot, RT-PCR, and 2'7'-dichlorofluorescein 3'6'-diacetate, respectively. The viability of podocytes was also assessed by MTT colorimetry in the present study. The expression of β1 integrin was significantly decreased, and the synthesis of ROS was significantly increased in podocytes following either PAN or H2O2 treatment (p < 0.05). The up-regulation of β1 integrin and down-regulation of ROS were also observed in PAN-treated podocytes following lower concentrations of FLV or SOD treatment (p < 0.05, respectively). The cytotoxicity data derived from MTT assay revealed that lower podocyte viability was found in the presence of higher concentrations of FLV, PAN, or H2O2. Lower concentration of FLV or SOD can protect podocytes from being impaired by PAN treatment. FLV attenuated the podocyte injury induced by PAN and increased the production of β1 integrin in human podocytes in vitro. This underlying mechanism of FLV may be through inhibiting the activity of ROS in human podocytes.

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

“…Rosuvastatin attenuated angiotensin II-dependent increases in NADPH oxidase activity and reactive oxygen species (ROS) generation in cultured podocytes [65]. In line with these findings are reports that fluvastatin is able to attenuate injury induced by PAN and to increase the production of β1-integrin in human podocytes in vitro, which is thought to be an ROS activity-inhibiting mechanism [66,67]. Rosuvastatin has also been found to display pro-survival activities in injured podocytes through a p21-dependent anti-apoptotic pathway [68].…”

“…Mitochondrial function [65], β-integrin [66,67] VEGF-R blocker Positive (diabetes) [86,87], negative (other glomerular disease) [80,81,88,89] Apoptosis, podocyte effacement, nephrin [79] PPARγ, peroxisome proliferator-activated receptor gamma; RAAS, renin-angiotensin-aldosterone system; ACE, angiotensin-converting enzyme; AT1-R, angiotensin II type 1 receptor; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA lyase reductase; VEGF-R, vascular endothelial growth factor receptors; SMPDL-3b, sphingomyelin phosphodiesterase, acid-like 3B…”

Plectin protects podocytes from adriamycin‐induced apoptosis and F‐actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway

“…Whereas the expression of integrin β1 in podocyte was considered negatively correlated with the severity of proteinuria . Elevated expression of TGF‐β1 or ROS induced decreased expression of integrin β1, resulting in the production of proteinuria . In contrast to the other β subunits, the integrin β4 subunit contains an exceptionally large cytoplasmic domain comprising several major tyrosine phosphorylation sites and thus regulates multiple intracellular signalling pathways .…”

Hepatitis B Virus X Protein Reduces Podocyte Adhesion via Downregulation of α3β1 Integrin

“…Podocytes play a crucial role in maintaining the permeability of the glomerular filtration barrier [14], and podocyte injury is present in many types of human and experimental glomerular diseases, including HBV-GN [4, 15-17]. Moreover, a decreased number of podocytes per glomerulus is the strongest predictor of renal disease progression [18].…”

“…Recent studies of integrin expression in podocytes demonstrated that α3β1 integrin is the major integrin on the surface of podocytes in humans [27] and rats [28]. This integrin is responsible for cell adhesion and signal transduction between podocytes and the extracellular matrix (ECM) of the glomerular basement membrane (GBM) [14]. Previous studies have shown that the absolute number and relative density of podocytes are reduced in HBV-GN [4], although the precise mechanism of this effect is unknown.…”