Angiotensin II Facilitates Fibrogenic Effect of TGF-β1 through Enhancing the Down-Regulation of BAMBI Caused by LPS: A New Pro-Fibrotic Mechanism of Angiotensin II

Abstract

Angiotensin II has progressively been considered to play an important role in the development of liver fibrosis, although the mechanism isn't fully understood. The aim of this study was to investigate a possible pro-fibrotic mechanism, by which angiotensin II would enhance the pro-fibrotic effect of transforming growth factor beta 1 (TGF-β1) through up-regulation of toll-like receptor 4 (TLR4) and enhancing down-regulation of TGF-β1 inhibitory pseudo-receptor—BAMBI caused by LPS in hepatic stellate cells (HSCs). Firstly, the synergistic effects of angiotensin II, TGF-β1 and LPS on collagen 1α production were confirmed in vitro by ELISA, in which angiotensin II, LPS and TGF-β1 were treated sequentially, and in vivo by immunofluorescence, in the experiments single or multiple intra-peritoneally implanted osmotic mini-pumps administrating angiotensin II or LPS combined with intra-peritoneal injections of TGF-β1 were used. We also found that only LPS and TGF-β1 weren't enough to induce obvious fibrogenesis without angiotensin II. Secondly, to identify the reason of why angiotensin II is so important, the minute level of TLR4 in activated HSCs - T6 and primary quiescent HSCs of rat, up-regulation of TLR4 by angiotensin II and blockage by different angiotensin II receptor type 1 (AT1) blockers in HSCs were assayed by western blotting in vitro and immunofluorescence in vivo. Finally, BAMBI expression level, which is regulated by LPS-TLR4 pathway, was detected by qRT-PCR and results showed angiotensin II enhanced the down-regulation of BAMBI mRNA caused by LPS in vitro and in vivo, and TLR4 neutralization antibody blocked this interactive effect. These data demonstrated that angiotensin II enhances LPS-TLR4 pathway signaling and further down-regulates expression of BAMBI through up-regulation of TLR4, which results in facilitation of pro-fibrotic activity of TGF-β1. Angiotensin II, LPS and TGF-β1 act synergistically during hepatic fibrogenesis, showing crosstalks between angiotensin II-AT1, LPS-TLR4 and TGF-β1-BAMBI signal pathways in rat HSCs.

Association of TGF-β1 and TNF-α genes polymorphisms with the kidney scars forming risk in children with vesicoureteral reflux

“…Many studies have dealt with the possible role of DNA polymorphisms in the renin-angiotensin system in progressive kidney damage. The data indicate that TGF-β1 and angiotensin II regulate the expression of each other (LI et al, 2013). All this supports the hypothesis that TGF-β1 might be an important factor in the pathogenesis of urinary tract infections, VUR and kidney scars.…”

Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis

“…Notably, disruption of the gene encoding BAMBI showed increased expression of fibrogenic markers in mice after BDL and prolonged TGF-b-induced HSC activation, which strongly supporting that BAMBI acts a protective factor in liver fibrosis and a negative regulator of HSC activation [11,49]. Furthermore, LPS [49], angiotensin II (Ang II) [51] and free cholesterol [52,53] could enhance down-regulation of BAMBI through the toll-like receptor 4 (TLR4), which sensitizes HSCs to TGF-b1 and promotes activation of HSC. Taken together, these data point that silence of BAMBI in HSC leads to unrestricted activation of TGF-b-induced signals and evident augment of TGF-b-mediated fibrogenic response of HSCs ultimately impairing liver function.…”

Dynamic Interstitial Cell Response during Myocardial Infarction Predicts Resilience to Rupture in Genetically Diverse Mice

“…Angiotensin II (AngII) induces a secretory phenotype in fibroblasts, stimulating the production of chemokines and ECM components (Bouzegrhane and Thibault, 2002), as well as pro-fibrotic factors, including TGF-b1 (Rosenkranz, 2004). AngII plays an essential role in promoting liver fibrosis by upregulating Toll-like receptor 4 (TLR4), thus enhancing downregulation of the TGF-b1 inhibitory pseudo-receptor BAMBI (Li et al, 2013). Consistently, our single-cell data showed a relative increase in Agt1ra, its downstream targets Tlr4, Tgfb1, and Ctgf ( Figure 7B), and reduced Bambi in 129 stromal cells post-MI ( Figures S8C and S9).…”