Transactivation domain of Krüppel‐like factor 15 negatively regulates angiotensin II–induced adventitial inflammation and fibrosis

Abstract

Krüppel‐like factor (KLF) 15 has emerged as a critical regulator of fibrosis in cardiovascular diseases. However, the precise role that KLF15 and its functional domain played in adventitial inflammation and fibrosis remains unclear. This study aims to investigate the role of the transactivation domain (TAD) of KLF15 in angiotensin II (Ang II)–induced adventitial pathologic changes. KLF15 expression was decreased in the vascular adventitia of Ang II–infused mice (1000 ng/kg/min, 14 d) and in adventitial fibroblasts (AFs) stimulated by Ang II (10−7 M). Adenovirus‐mediated KLF15 overexpression normalized Ang II–induced vascular hypertrophy, increased collagen deposition, macrophage infiltration, and CCL2 and VCAM‐1 expression. Interestingly, KLF15‐ΔTAD (KLF15 with deletion of TAD at amino acids 132–152) overexpression showed no effect on the above pathologic changes. Similarly, perivascularly over‐expression of KLF15 but not KLF15‐ΔTAD in carotid arteries also attenuated Ang II–induced vascular inflammation and fibrosis. Furthermore, KLF15 overexpression after Ang II infusion rescued Ang II–induced vascular remodeling. CCL2 or VCAM‐1–mediated monocyte and macrophage migration or adhesion to AFs in response to Ang II was negatively regulated by KLF15 through TAD. Ang II–enhanced Smad2/3 activation and adventitial migration, proliferation, and differentiation of AFs were suppressed by KLF15 but not KLF15‐ΔTAD overexpression. Conversely, small interfering RNA knockdown of KLF15 aggravated Ang II–induced Smad2/3 activation and dysfunction of AFs. Luciferase, coimmunoprecipitation, and chromatin immunoprecipitation assay were used to demonstrate that interaction of KLF15 with Smad2/3 suppressed CCL2 expression through TAD. Mechanistically, activation of Ang II type 1 receptor/phospholipase Cγ 1/ERK1/2 signaling resulted in a decrease of KLF15 expression. In conclusion, these results demonstrate that KLF15 negatively regulates activation of AFs through TAD, which plays an important role in Ang II–induced adventitial inflammation and fibrosis.—Lu, Y.‐Y., Li, X.‐D., Zhou, H.‐D., Shao, S., He, S., Hong, M.‐N., Liu, J.‐C., Xu, Y.‐L., Wu, Y.‐J., Zhu, D.‐L., Wang, J.‐G., Gao, P.‐J. Transactivation domain of Krüppel‐like factor 15 negatively regulates angiotensin II–induced adventitial inflammation and fibrosis. FASEB J. 33, 6254–6268 (2019). http://www.fasebj.org

Chronic intermittent hypoxia promotes glomerular hyperfiltration and potentiates hypoxia-evoked decreases in renal perfusion and PO2

“…In particular we focused on pathways related to tissue hypoxia because of its relevance to our physiological measurements. KLF15, and E-Cadherin, which have fibrosis-suppressing activity and have been shown to be downregulated by ANG II and hypoxia ( Esteban et al, 2006 ; Lu et al, 2019 ), were decreased in cortical tissue from CIH relative to sham. Expression of pro-fibrotic CTGF, TIMP, Galectin 3, Snail, and VEGF (all of which are induced by hypoxia and/or ANG II ( Liu et al, 2017 ; Boutin et al, 2022 ; Khalaji et al, 2023 )), was significantly higher in cortical tissue from CIH vs sham, suggesting that CIH exposure promotes activation of pro-oxidative, pro-fibrotic signaling that may contribute to tissue damage and organ dysfunction.…”

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

“…Second, HDACs, in addition to removing the acetyl group from histones, can also de-acetylate non-histone proteins. The class III HDAC SIRT1 mitigates renal fibrosis, in part, by deacetylating and deactivating SMAD3, a key transcription factor involved in fibrogenesis (Li et al, 2010). HDAC1 and HDAC2 can promote the deacetylation of STAT1, which prevents its binding to and inhibition of NF-κB allowing the latter to stimulate a pro-fibrogenic transcription program in mesangial cells (Kumar et al, 2017).…”

Identification of Novel Targets of Knee Osteoarthritis Shared by Cartilage and Synovial Tissue

“…Moreover, KLF15 could reduce the TNF-α-induced expression of MMP-3, a well-known cartilage-degrading enzyme [ 70 ]. On the other hand, KFL15 activation could negatively regulate inflammations in several cell types [ 72 , 73 , 74 , 75 ]. Thus, elevating KLF15 levels in OA may also achieve the dual effects of pro-chondrogenesis and anti-inflammation.…”