Activation of MST1 protects filtration barrier integrity of diabetic kidney disease in mice through restoring the tight junctions of glomerular endothelial cells

Article

Author: Jiang, Zhen-Zhou ; Qian, Si-Tong ; Shao, Yu-Ting ; Yin, Xiao-Xing ; Li, Lin ; Pan, Dan-Dan ; Wang, Tao ; Liu, Jun-Jie ; Li, Bao-Jing ; Yang, Ting-Ting ; Liu, Ying ; Heng, Cai ; Zhu, Xia ; Yan, Meng ; Lu, Qian

As a pathological feature of diabetic kidney disease (DKD), dysregulated glomerular filtration barrier function could lead to the increased levels of proteinuria. The integrity of tight junctions (TJs) of glomerular endothelial cells (GECs) is a guarantee of physiological function of glomerular filtration barrier. Mammalian sterile 20-like kinase (MST1) is a key regulatory protein in the blood-brain barrier (BBB), and it regulates the expression of TJs-related proteins in cerebral vascular endothelial cells. Our previous study showed that MST1 was involved in renal tubulointerstitial fibrosis of DKD. In the present study we investigated the role of MST1 in barrier function of GECs of DKD, and explored its regulatory mechanisms. In kidney tissue section of DKD patients and db/db mice, and high glucose (HG)-cultured mouse glomerular endothelial cells (mGECs), we showed that MST1 was inactivated in the GECs of DKD accompanied by disrupted glomerular endothelial barrier. In db/db mice and HG-cultured mGECs, knockdown of MST1 increased proteinuria levels, and disrupted glomerular endothelial barrier through decreasing TJs-related proteins, whereas MST1 overexpression restored glomerular endothelial barrier through regaining TJs-related proteins. In db/db mice and HG-cultured mGECs, we demonstrated that MST1 inhibition induced TJs's disruption of GECs via activating YAP1/TEAD signaling. Verteporfin (an inhibitor of YAP1-TEAD interaction) and PY-60 (a YAP1 agonist) were used to verify the role of YAP1/TEAD signaling in the regulation effect of MST1 on barrier function of mGECs. In conclusion, MST1 activation recovers glomerular endothelial barrier of DKD by regaining TJs-related proteins via inhibiting YAP1/TEAD signaling. This study highlights the multiple regulation of MST1 activation on kidney injury.

01 Mar 2025·Journal of Ethnopharmacology

Gancao Xiexin decoction attenuated experimental colitis through suppressing ACSL4-mediated ferroptosis

Article

Author: Yang, Yali ; Li, Lihai ; Zhang, Shengyuan ; Zhi, Shaobin ; Huang, Qionghui ; Gan, Caiyan ; Pan, Zengfeng ; Zhang, Yinmei

ETHNOPHARMACOLOGICAL RELEVANCEThe Gancao Xiexin decoction (GCXXD), comprising Glycyrrhiza glabra L., Pinellia ternata (Thunb.) Makino, Scutellaria baicalensis Georgi, Zingiber officinale Roscoe, Panax ginseng C.A.Mey. , Coptis chinensis Franch. , Ziziphus jujuba Mill. , represents a traditional Chinese medicinal formulation utilized for the treatment of ulcerative colitis (UC). Nevertheless, the potential mechanism behind GCXXD treatment for UC is not yet fully elucidated.AIM OF THE STUDYUlcerative colitis is a chronic inflammatory disorder of the gastrointestinal system distinguished by intestinal barrier destruction. Previous studies have indicated that excessive ferroptosis activation in intestinal epithelial cells (IECs) can worsen damage and focal permeability abnormalities in the colon. One of the main mechanisms of ferroptosis is lipid peroxides, which are dependent on long-chain acyl-CoA synthetase 4 (ACSL4) for the synthesis of membrane phospholipids. Recent research findings have provided evidence that GCXXD significantly reduces the symptoms of ulcerative colitis (UC) by preserving the intestinal mucosal barrier. So, we aim to demonstrate that the pharmacological mechanism of GCXXD is related to ferroptosis mediated by ACSL4 in this research.MATERIALS AND METHODSIn this investigation, we evaluated the GSE134025 datasets and established an experimental colitis model caused by DSS and treated with a 20 mg/kg ACSL4 inhibitor (rosiglitazone). Colon pathological alterations and Alcian blue staining were used to confirm ACSL4 inhibition as a possible therapy for UC. We then examined illness symptoms, intestinal mucosa repair, and ferroptosis markers in UC mice after treated with GCXXD (9,12,15 g/kg). Transcriptome study of colon tissues revealed more about the underlying mechanism of GCXXD in the treatment of UC. Finally, we co-administered the ACSL4 upstream agonist with GCXXD in the treatment of UC to show that GCXXD reduced inflammation in UC by modifying ACSL4-induced ferroptosis.RESULTSThrough GSE134025 dataset analysis, we discovered that ACSL4 was substantially expressed in UC patients and that its inhibitors successfully reduced the clinical signs and symptoms of UC colon. Furthermore, we found that GCXXD improved colon length and body weight while increasing the expression of mucin, occuldin, and Claudin-1. It also lowered colon inflammatory cell infiltration and levels of IL-1β and TNF-α. In the meantime, GCXXD efficiently decreased ferroptosis-related indicators in colitis mice, such as MDA, Fe²⁺, COX2, and ACSL4, while also upregulated GPX4 expression. Using KEGG analysis of the genes that were differently expressed between the 3% DSS and GCXXD treatment group, we were able to discover important connections between the hippo signaling pathway, Arachidonic acid metabolism with GCXXD treatment. Due to the fact that TEAD4 functions as an upstream transcription factor for ACSL4, we combined GCXXD and Py-60, a YAP agonist in the treatment of UC. It was worth noting that GCXXD's inhibitory effect of on intestinal mucosa damage and ferroptosis was lessened when the ACSL4 upstream pathway was activated.CONCLUSIONGancao Xiexin decoction attenuated ferroptosis in UC which might through TEAD4/ACSL4 pathway.

13 Jan 2025·International Journal of Biological Sciences

Tetramethylpyrazine attenuates sodium arsenite-induced acute kidney injury by improving the autophagic flux blockade via a YAP1-Nrf2-p62-dependent mechanism

Article

Author: Song, Zhiyong ; Hei, Tom K ; Gong, Xuezhong

With increased application, sodium arsenite (AS III)-induced acute kidney injury (AI-AKI) is becoming a new clinical challenge, but its potential pathogenesis remains poorly studied. Our previous data demonstrated that inducing autophagy and mitochondrial dysfunction in renal tubular cells are important links of AI-AKI and could be inhibited by tetramethylpyrazine (TMP). Recently, co-transcription factor YAP1 is reported to control autophagy and is mandatory to stimulate autophagic flux. This study constructed in vitro and in vivo models using clinically related dosages of AS III. Mitophagy, upregulated YAP1 expression, and Nrf2 activation were observed, with upregulation of p62 representing the occurrence of autophagic flux blockade. In HK-2 cells, oxidative stress induced by AS III promoted sustained Nrf2 activation, which enhanced p62 transcription at an early phase. Subsequently, p62 accumulation induced Nrf2 nuclear translocation, which in turn promoted p62 expression, forming a feedback loop to induce autophagic flux blockade, which was aggravated by the autophagic flux blocker chloroquine (CQ). TMP reversed such processes and protected tubular cells, while silencing YAP1 and Nrf2 attenuated TMP renoprotections. YAP1 agonist PY-60 increased Nrf2 expression, while YAP1 knockdown counteracted it and diminished TMP effect on autophagic flux. Furthermore, blocking Nrf2 caused YAP1 accumulation. CO-IP and immunofluorescence co-localization results confirmed co-nuclear translocations of YAP1 bound to dissociated Nrf2 that induced autophagic flux blockade. In conclusion, the present study identified novel mechanisms that TMP alleviated AI-AKI by improving the autophagic flux blockade via a YAP1-Nrf2-p62-dependent mechanism.

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