title: Candesartan inhibits LPS-induced expression increase of toll-like receptor 4 and downstream inflammatory factors likely via angiotensin II type 1 receptor independent pathway in human renal tubular epithelial cells.
abstract: The present study was to determine whether candesartan, an angiotensin II type 1 receptor blocker (ARB), exerts anti-inflammatory effects through inhibiting the toll-like receptor 4 (TLR4) pathway in human renal tubular epithelial cells (HKCs). The experiments were carried on cultured HKCs. By means of flow cytometry, Western blot, RT-PCR and ELISA techniques, the TLR4 protein, angiotensin II type 1 receptor (AT1R) and phosphorylated nuclear factor-kappa B (NF-κB) p65 protein level, mRNA levels of macrophage chemoattractant protein-1 (MCP-1) and regulated upon expression normal T cell expressed and secreted (RANTES), as well as MCP-1 and RANTES protein concentrations in conditioned media were measured. The results showed that lipopolysaccharide (LPS) upregulated the TLR4 protein level in cultured HKCs. Application of LPS increased NF-κB activation and induced release of its downstream inflammatory factors including MCP-1 and RANTES. Candesartan reversed LPS-induced upregulation of TLR4 expression, inhibited NF-κB activation, and reduced MCP-1 and RANTES release. However, knockdown on AT1R by siRNA did not change those previous effects of candesartan. These results suggest that candesartan-induced anti-inflammatory effect may be through a novel pathway, independent of AT1R.
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Central Laboratory, East Hospital, Tongji University School of Medicine, Shanghai 200120, China. yuchen2001@hotmail.com.
authors.forename: Li-Qin
authors.initials: LQ
authors.lastname: Zhao
authors.forename: Jie-Li
authors.initials: JL
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Lan-Jun
authors.initials: LJ
authors.lastname: Fu
authors.forename: Jun-Ling
authors.initials: JL
authors.lastname: Wang
authors.forename: Yan-Dao
authors.initials: YD
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Yu
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology; D008070:Lipopolysaccharides; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; C495345:TLR4 protein, human; D013777:Tetrazoles; D051197:Toll-Like Receptor 4; C081643:candesartan