Frontiers in Medicine
·
2024
·
IF 3.1
Liu Yan,Ge Ri-Li,Shan Zhen-Zhen,Wang Yan-Jun,Yang Yan-Yan,Sun Xue,Luo Peng-Li
Podocytopathies encompass kidney diseases where direct or indirect podocyte injury leads to proteinuria or nephrotic syndrome. Although Semaphorin3A (Sema3A) is expressed in podocytes and tubular cells in adult mammalian kidneys and has a common effect on the progression of podocyte injury, its mechanism remains unclear. Previous studies have shown increased Sema3A expression in various glomerulopathies, indicating a gap in understanding its role. In this study, analysis of human data revealed a positive correlation between the levels of urinary Sema3A and Podocalyxin (PCX), suggesting a close relationship between Sema3A and podocyte loss. Furthermore, the impact of Adriamycin on podocytes was investigated. Adriamycin induced podocyte migration and apoptosis, along with an increase in Sema3A expression, all of which were ameliorated by the inhibition of Sema3A. Importantly, TRPC5 was found to increase the overexpression of Sema3A in podocytes. A TRPC5 inhibitor, AC1903, alleviated podocyte migration and apoptosis, inhibiting the formation of lamellar pseudopodia in the podocyte cytoskeleton by lowering the expression of Rac1. Furthermore, AC1903 relieved massive albuminuria and foot process effacement in the kidneys of Adriamycin-treated mice in vivo. In conclusion, our findings suggest that Sema3A may impact the cytoskeletal stability of podocytes through TRPC5 ion channels, mediated by Rac1, ultimately leading to foot process effacement. Notably, AC1903 demonstrates the potential to reverse Adriamycin-induced foot process fusion and urine protein. These results contribute to a deeper understanding of the mechanisms involved in podocytopathies and highlight the therapeutic potential of targeting the Sema3A-TRPC5 pathway.
研究领域:
肾脏病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2024
·
IF 8.2
Suyun Yu,Rui Deng,Wei Wang,Defang Zou,Liang He,Zhonghong Wei,Yanhong Pan,Xiaoman Li,Yuanyuan Wu,Aiyun Wang,Wenxing Chen,Yang Zhao,Yin Lu
The thermo-sensory receptor, transient receptor potential channel 5 (TRPC5), a non-selective calcium ion (Ca 2+ )-permeable ion channel, has been implicated in cancer initiation and progression. However, its specific role in gastrointestinal cancer remains unclear. This study demonstrates that TRPC5 is significantly overexpressed in gastrointestinal tumors and is inversely associated with patient prognosis. TRPC5 overexpression triggers a substantial elevation in intracellular Ca 2+ levels ([Ca 2+ ]i), driving actin cytoskeleton reorganization and facilitating filopodia formation. Furthermore, kaempferol, a compound sourced from traditional Chinese medicine, is identified as a TRPC5 inhibitor that effectively suppresses its activity, thereby impeding gastrointestinal cancer metastasis. These findings underscore the potential of TRPC5 as a therapeutic target for metastasis inhibition, with kaempferol emerging as a promising natural inhibitor that could be optimized for clinical use in preventing cancer metastasis.
研究领域:
肿瘤学
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药理学
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Science Advances
·
2019
·Vol. 5
·期 7
·
IF 12.804
Jingjing Duan,Jian Li,Gui-Lan Chen,Yan Ge,Jieyu Liu,Kechen Xie,Xiaogang Peng,Wei Zhou,Jianing Zhong,Yixing Zhang,Jie Xu,Changhu Xue,Bo Liang,Lan Zhu,Wei Liu,Cheng Zhang,Xiao-Li Tian,Jianbin Wang,David E. Clapham,Bo Zeng,Zongli Li,Jin Zhang
The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-Å resolution cryo–electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.
研究领域:
结构生物学
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药理学
·
神经科学
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DOI
PubMed
高影响因子
Fundamental Research
·
2022
·
IF 0
Yifei Zhu,Sheng Wang,Yuan Chu,Ka Zhang,Xin Wen,Lei Feng,Fan Yu,Xin Ma
The role of the Ca 2+ -permeable ion channel TRPC5 in regulating vasocontraction in obesity is poorly understood. Here, we investigated whether TRPC5 contributes to vascular dysfunction in obesity by promoting endothelium-dependent contraction via activation of cytosolic phospholipase A2 (cPLA 2 ) in the aortic endothelial cells of obese mice. Acetylcholine-induced endothelium-dependent relaxation and contraction in the aorta were measured using wire myography. PLA 2 activity was measured by the fluorogenic PLA 2 substrate Bis-BODIPY™ FL C 11 -PC. The intracellular Ca 2+ level in response to acetylcholine was measured by Fluo-4 fluorescence. Endothelium-derived contracting factors were assessed by enzyme immunoassay. Diet-induced obesity (DIO) attenuated endothelium-dependent vasodilation, enhanced endothelium-dependent contraction (EDC), and increased the expression of TRPC5 in the mouse aorta. Activation of TRPC5 promoted EDC in the wild-type mouse aorta, whereas pharmacological inhibition and genetic knockout of TRPC5 decreased EDC in the DIO mouse aorta. Moreover, cPLA 2 phosphorylation and activity were higher in aortic endothelial cells from DIO mice, and this was attenuated by inhibition and knockout of TRPC5. Cyclooxygenase 2 (COX-2) expression was increased in DIO mouse endothelium and was decreased by a TRPC5 inhibitor and knockout of TRPC5. Release of prostaglandins F 2α (PGF 2α ) and E 2 (PGE 2 ) was involved in TRPC5-regulated EDC in DIO mice. This study demonstrated that TRPC5 contributes to endothelial and vascular dysfunction and is involved in EDC through activation of cPLA 2 and enhanced COX-2-PGF 2α /PGE 2 levels in DIO mice.
研究领域:
药理学
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心血管生理学
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分子生物学
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DOI
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
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IF 6
Yuanyuan Xu,Younan Ren,Jie Zhang,Bo Niu,Mengru Liu,Tifei Xu,Xian Zhang,Jianhua Shen,Kai Wang,Zhengyu Cao
Transient receptor potential canonical 5 (TRPC5) is a calcium-permeable non-selective cation channel involved in various pathophysiological processes, including renal injury. Recently, GFB-887, an investigational pyridazinone TRPC5 inhibitor, demonstrated significant therapeutic potential in a Phase II clinical trial for focal segmental glomerulosclerosis (FSGS), a rare and severe form of chronic kidney disease (CKD). In the current study, based on the structure of GFB-887, we conducted extensive structural modification to explore novel TRPC5 inhibitors with desirable drug-like properties and robust nephroprotective efficacy. A series of pyridazinone derivatives featuring a novel tetrahydroimidazo[1,2- a ]pyrazine scaffold were synthesized and their activities were evaluated in HEK-293 cells stably expressing TRPC5 using a fluorescence-based Ca 2+ mobilization assay. Among these compounds, compound 12 is turned out to be a potent TRPC5 inhibitor with apparent affinity comparable to the parent compound GBF-887. Compound 12 is highly selective on TRPC4/5 over TRPC3/6/7 and hERG channels, along with acceptable pharmacokinetic properties and a favorable safety profile. More importantly, in a rat model of hypertension-induced renal injury, oral administration of compound 12 (10 mg/kg, BID) efficaciously reduced mean blood pressure, inhibited proteinuria, and protected podocyte damage. These findings further confirmed the potential of TRPC5 inhibitors on the CKD treatment and provided compound 12 to be a valuable tool for exploring TRPC4/5 pathophysiology.
研究领域:
药理学
·
分子生物学
·
肾脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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