Suppression of Elp2 prevents renal fibrosis and inflammation induced by unilateral ureter obstruction (UUO) via inactivating Stat3-regulated TGF-β1 and NF-κB pathways.

Abstract

Renal fibrosis and inflammation are common underlying processes of progressive kidney diseases. Elongator protein 2 (Elp2), identical to signal transducer and activator of transcription-3 (STAT-3)-interacting protein-1 (Stip1), is a component of the Elongator complex that regulates RNA polymerase II. Elp2 regulates STAT-3 activation to control various cellular processes. The mechanisms of Elp2 prevention in renal interstitial fibrosis and inflammation remain unknown. In the study, Elp2 transgenic knockout (KO) and wild type (WT) mice were employed to investigate the effects of Elp2 on renal fibrosis and inflammation development after unilateral ureter obstruction (UUO) surgery. The results indicted that Elp2 was significantly expressed in renal tissues of WT/UUO mice. Elp2-KO mice exhibited attenuated histological changes of kidney, as well as collagen and fibrosis accumulation. Lower expressions of transforming growth factor (TGF)-β1, α-smooth muscle actin (α-SMA), fibronectin, vimentin, and phospho-Smad2/3 were observed in kidney of Elp2-KO mice than that of WT mice after UUO. Elp2-KO mice showed less inflammation, as evidenced by the decrease of circulating or renal pro-inflammatory cytokines, as well as the reduction of phospho-nuclear factor (NF)-κB. Additionally, Elp2-KO apparently led to a decrease in phospho-STAT3 in kidney of UUO mice. In vitro, we found that TGF-β1- and LPS-induced fibrosis and inflammation were abrogated by Elp2 knockdown, which were intriguingly abolished by activating STAT3 phosphorylation using its activator of colivelin (Col). Together, our findings supplied that Elp2 might be a potential therapeutic target to prevent the progression of renal fibrosis and inflammation.

• Authors: Shan Lu, Hong-Wu Fan, Kai Li, Xiao-Di Fan
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 501 Issue 2 Pg. 400-407 (06 22 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29723529 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier Inc.

Chemical References

• Elp2 protein, mouse
• Intracellular Signaling Peptides and Proteins
• Lipopolysaccharides
• NF-kappa B
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Transforming Growth Factor beta1

Topics

• Animals
• Disease Models, Animal
• Fibrosis (genetics, pathology)
• Intracellular Signaling Peptides and Proteins (genetics, physiology)
• Kidney (metabolism, pathology)
• Kidney Tubules (drug effects, metabolism, pathology)
• Lipopolysaccharides (pharmacology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Nephritis (metabolism, pathology)
• STAT3 Transcription Factor (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Ureteral Obstruction (complications, metabolism, physiopathology)