Inhibitory Effects of Rosiglitazone on Lipopolysaccharide-Induced Inflammation in a Murine Model and HK-2 Cells

Abstract

Background: Inflammation may play an important role in the pathogenesis of kidney disease. Agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as rosiglitazone, have been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators. The purpose of this study was to examine the effects of rosiglitazone on lipopolysaccharide (LPS)-induced kidney inflammation and to explore the mechanism of its renoprotection. Methods: Mice were treated with LPS with or without pretreatment with rosiglitazone. Blood urea nitrogen (BUN), creatinine levels, the urinary albumin-to-creatinine ratio, macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, PPAR-γ expression, and NF-ĸB and PPAR-γ activity were investigated. HK-2 cells were maintained under defined in vitro conditions, treated with either rosiglitazone and/or the PPAR-γ antagonist GW9662, and then stimulated with LPS. MCP-1, IL-8, IL-6, NF-ĸB activity and PPAR-γ expression were investigated. Results: Compared to the LPS only group, pretreatment with rosiglitazone in vivo significantly attenuated the BUN levels macrophage infiltration, MCP-1 overexpression and NF-ĸB activity (p < 0.05). Rosiglitazone also restored PPAR-γ expression and protein activity, which were reduced significantly in the LPS only group (p < 0.05). Furthermore, in the LPS-stimulated HK-2 cells, rosiglitazone downregulated MCP-1, IL-8 and IL-6 expression as well as NF-ĸB activation and increased PPAR-γ expression (p < 0.05). These effects were diminished by GW9662. Conclusion: These results showed that pretreatment with rosiglitazone could attenuate kidney inflammation through the activation of PPAR-γ, suppression of MCP-1 overproduction and NF-ĸB activation. Rosiglitazone had a protective effect via a PPAR-γ-dependent pathway in LPS-treated HK-2 cells.

Squalene targets pro- and anti-inflammatory mediators and pathways to modulate over-activation of neutrophils, monocytes and macrophages

“…Therefore, we investigated the influence of squalene on gene expression of three major MMPs (MMP-1, MMP-3 and MMP-9). As PPARγ agonists have been shown to inhibit LPS-mediated MMPs and pro-inflammatory cytokines (Renga et al, 2011;Wang et al, 2011), our study also undertook to explore whether squalene can affect PPARγ gene expression in LPS-treated cells. As shown in Fig.…”

PPARs in Regulation of Paraoxonases: Control of Oxidative Stress and Inflammation Pathways

“…This compound also counteracts tumor necrosis factor-induced inhibition of PPAR γ expression in these cells [88]. Rosiglitazone, which is a ligand for PPAR γ , inhibits inflammation and reduces MCP-1 production by murine cells [89] and has similar effects on lipopolysaccharide-treated mice and HK-2 cells [90]. Finally, telmisartan, an angiotensin type I receptor blocker, increases PPAR γ activity and PPAR ligand-binding activity, reduces atherosclerosis in mouse macrophages [91], and reduces MCP-1 production by peripheral monocytes in patients with essential hypertension [92].…”

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

“…PPARc is expressed in all glomerular and tubular cells [9,10]. In addition to a well-defined antihyperglycemic role for PPARc agonists, our previous studies also described a protective role in diabetic and nondiabetic kidney injury for various renal cells, the mechanism of which was independent of the hyperglycemic regulation, and instead functioned primarily through regulation of inflammatory and metabolic-related pathways [11,12]. However, the specific molecules regulated by PPARc during inflammatory and metabolic processes remain unclear.…”