cGAS-STING通路在肾脏疾病中的研究进展

韩振元; 王晓燕

doi:10.16766/j.cnki.issn.1674-4152.003304

cGAS-STING通路在肾脏疾病中的研究进展

doi: 10.16766/j.cnki.issn.1674-4152.003304

韩振元¹,
王晓燕^{1, 2, ,}

1.
南京医科大学附属明基医院肾脏内科，江苏南京 210019
2.
南京医科大学附属明基医院中心实验室

基金项目:

国家自然科学基金项目 81970605

详细信息

通讯作者:
王晓燕，E-mail：xiaoyan.wang@benqmedicalcenter.com

中图分类号: R692
计量
- 文章访问数: 159
- HTML全文浏览量: 53
- PDF下载量: 13
- 被引次数: 0
出版历程
- 收稿日期: 2023-06-08
- 网络出版日期: 2024-01-29

Research progress on the cGAS-STING pathway in the kidney disease

HAN Zhenyuan¹,
WANG Xiaoyan^{1, 2
, ,}

1.
Department of Nephrology, the Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu 210019, China

摘要

摘要: 环鸟苷酸腺苷酸合成酶-干扰素基因刺激因子(cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes，cGAS-STING)信号通路作为先天免疫系统的重要组成部分，通过激活干扰素调节因子3或核因子-κB，促进Ⅰ型干扰素和炎性因子分泌介导免疫反应，在炎症、感染、细胞稳态、肥胖及器官纤维化发生发展中发挥着重要作用。同时，临床和基础医学研究者日益重视起cGAS-STING通路在肾脏常见疾病中的作用。研究表明，在急性肾损伤中，cGAS-STING通路的激活可以加剧炎症反应；而在慢性肾脏病中，其异常激活与肾脏纤维化的发生和发展密切相关。此外，cGAS-STING通路在肾癌中也发挥着重要的作用。因此，cGAS-STING通路可能成为治疗相关肾脏疾病的新靶点。然而，目前对于cGAS-STING通路在肾脏疾病中的具体作用机制和治疗潜力还需要进一步的研究。为了给临床医生和研究者提供新的思路，本文回顾了近年来cGAS-STING通路在常见肾脏疾病如急性肾损伤、慢性肾脏病、肾癌等方面的研究进展，并强调了该通路作为针对急性肾损伤有效治疗靶点的意义，为肾脏疾病的治疗提供新的视角和方法。
- 环鸟苷酸腺苷酸合成酶-干扰素基因刺激因子 /
- 急性肾损伤 /
- 慢性肾脏病 /
- 肾癌
Abstract: As an important component of the innate immune system, the cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING) signaling pathway plays a critical role in mediating immune responses by inducing the secretion of type Ⅰ interferons and inflammatory cytokines. The cGAS-STING pathway activates interferon regulatory factor 3 or nuclear factor-κB and is involved in inflammation, infection, cellular homeostasis, obesity and organ fibrosis. In addition, the role of the cGAS-STING pathway in common kidney diseases is increasingly appreciated by clinical and basic researchers. Recent studies have shown that activation of the cGAS-STING pathway in acute kidney injury can trigger the release of inflammatory factors and exacerbate inflammation. This abnormal activation of the pathway is closely linked to the development and progression of kidney fibrosis in chronic kidney disease. In addition, the cGAS-STING pathway also plays an important role in kidney cancer. The cGAS-STING pathway is therefore a promising target for the treatment of kidney diseases. However, more research is needed to fully understand the specific mechanisms and therapeutic potential of the cGAS-STING pathway in kidney disease. In order to provide clinicians and researchers with new perspectives, this paper reviews recent research progress on the cGAS-STING pathway in common kidney diseases, discusses the role of this pathway in the pathogenesis of acute kidney injury, chronic kidney disease and renal cancer, and highlights the potential of this pathway as an effective therapeutic target, especially for acute kidney injury, in an attempt to provide new insights and approaches for the treatment of kidney diseases.
- Cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes /
- Acute kidney injury /
- Chronic kidney disease /
- Renal cancer

HTML全文

图 1 cGAS-STING通路的信号传导

Figure 1. Signal transduction in the cGAS/STING pathway

下载: 全尺寸图片幻灯片

参考文献(38)

[1]	MAEKAWA H, INOUE T, JAO T M, et al. Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury[J]. SSRN Electron J, 2019, 29(5): 1261-1273.e6.
[2]	MITROFANOVA A, FONTANELLA A, TOLERICO M, et al. Activation of stimulator of IFN genes (STING) causes proteinuria and contributes to glomerular diseases[J]. J Am Soc Nephrol, 2022, 33(12): 2153-2173. doi: 10.1681/ASN.2021101286
[3]	JI F, ZHANG F, ZHANG M, et al. Targeting the DNA damage response enhances CD70 CAR-T cell therapy for renal carcinoma by activating the cGAS-STING pathway[J]. J Hematol Oncol, 2021, 14(1): 152. doi: 10.1186/s13045-021-01168-1
[4]	HOPFNER K P, HORNUNG V. Molecular mechanisms and cellular functions of cGAS-STING signalling[J]. Nat Rev Mol Cell Biol, 2020, 21(9): 501-521. doi: 10.1038/s41580-020-0244-x
[5]	CHEN C, XU P L. Cellular functions of cGAS-STING signaling[J]. Trends Cell Biol, 2023, 33(8): 630-648. doi: 10.1016/j.tcb.2022.11.001
[6]	DING C, SONG Z, SHEN A, et al. Small molecules targeting the innate immune cGAS-STING-TBK1 signaling pathway[J]. Acta Pharm Sin B, 2020, 10(12): 2272-2298. doi: 10.1016/j.apsb.2020.03.001
[7]	LI T, CHEN Z J. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer[J]. J Exp Med, 2018, 215(5): 1287-1299. doi: 10.1084/jem.20180139
[8]	GUAN J, TONG X, ZHANG Y, et al. Nephrotoxicity induced by cisplatin is primarily due to the activation of the 5-hydroxytryptamine degradation system in proximal renal tubules[J]. Chem Biol Interact, 2021, 349: 109662. doi: 10.1016/j.cbi.2021.109662
[9]	KELLUM J A, ROMAGNANI P, ASHUNTANTANG G, et al. Acute kidney injury[J]. Nat Rev Dis Primers, 2021, 7(1): 52. doi: 10.1038/s41572-021-00284-z
[10]	MCSWEENEY K R, GADANEC L K, QARADAKHI T, et al. Mechanisms of cisplatin-induced acute kidney injury: pathological mechanisms, pharmacological interventions, and genetic mitigations[J]. Cancers(Basel), 2021, 13(7): 1572.
[11]	QI J, LUO Q, ZHANG Q, et al. Yi-Shen-Xie-Zhuo formula alleviates cisplatin-induced AKI by regulating inflammation and apoptosis via the cGAS/STING pathway[J]. J Ethnopharmacol, 2023, 309: 116327. doi: 10.1016/j.jep.2023.116327
[12]	LUO S, YANG M, HAN Y, et al. beta-Hydroxybutyrate against Cisplatin-Induced acute kidney injury via inhibiting NLRP3 inflammasome and oxidative stress[J]. Int Immunopharmacol, 2022, 111: 109101. doi: 10.1016/j.intimp.2022.109101
[13]	NIEUWENHUIJS-MOEKE G J, PISCHKE S E, BERGER S P, et al. Ischemia and reperfusion injury in kidney transplantation: relevant mechanisms in injury and repair[J]. J Clin Med, 2020, 9(1): 253. doi: 10.3390/jcm9010253
[14]	CAO J Y, WANG B, TANG T T, et al. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury[J]. Theranostics, 2021, 11(11): 5248-5266. doi: 10.7150/thno.54550
[15]	LIVINGSTON M J, SHU S, FAN Y, et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis[J]. Autophagy, 2023, 19(1): 256-277. doi: 10.1080/15548627.2022.2072054
[16]	PABLA N, BAJWA A. Role of mitochondrial therapy for ischemic-reperfusion injury and acute kidney injury[J]. Nephron, 2022, 146(3): 253-258. doi: 10.1159/000520698
[17]	TANG C, HAN H, YAN M, et al. PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury[J]. Autophagy, 2018, 14(5): 880-897. doi: 10.1080/15548627.2017.1405880
[18]	LI J, SUN X, YANG N, et al. Phosphoglycerate mutase 5 initiates inflammation in acute kidney injury by triggering mitochondrial DNA release by dephosphorylating the pro-apoptotic protein Bax[J]. Kidney Int, 2023, 103(1): 115-133. doi: 10.1016/j.kint.2022.08.022
[19]	FENG Y, IMAM ALIAGAN A, TOMBO N, et al. RIP3 translocation into mitochondria promotes mitofilin degradation to increase inflammation and kidney injury after renal ischemia-reperfusion[J]. Cells, 2022, 11(12): 1894. doi: 10.3390/cells11121894
[20]	LIAO Y, CHENG J, KONG X, et al. HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway[J]. Theranostics, 2020, 10(21): 9644-9662. doi: 10.7150/thno.47651
[21]	LEI C, TAN Y, NI D, et al. cGAS-STING signaling in ischemic diseases[J]. Clin Chim Acta, 2022, 531: 177-182. doi: 10.1016/j.cca.2022.04.003
[22]	CHUNG K W, DHILLON P, HUANG S, et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis[J]. Cell Metab, 2019, 30(4): 784-799.e5. doi: 10.1016/j.cmet.2019.08.003
[23]	FU H, LIU S, BASTACKY S I, et al. Diabetic kidney diseases revisited: a new perspective for a new era[J]. Mol Metab, 2019, 30: 250-263. doi: 10.1016/j.molmet.2019.10.005
[24]	TUTTLE K R, AGARWAL R, ALPERS C E, et al. Molecular mechanisms and therapeutic targets for diabetic kidney disease[J]. Kidney Int, 2022, 102(2): 248-260. doi: 10.1016/j.kint.2022.05.012
[25]	HUANG T S, WU T, WU Y D, et al. Long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice[J]. Nat Commun, 2023, 14(1): 390. doi: 10.1038/s41467-023-35944-z
[26]	STENVINKEL P, CHERTOW G M, DEVARAJAN P, et al. Chronic inflammation in chronic kidney disease progression: role of Nrf2[J]. Kidney Int Rep, 2021, 6(7): 1775-1787. doi: 10.1016/j.ekir.2021.04.023
[27]	ZANG N, CUI C, GUO X, et al. cGAS-STING activation contributes to podocyte injury in diabetic kidney disease[J]. iScience, 2022, 25(10): 105145. doi: 10.1016/j.isci.2022.105145
[28]	CHEN X, HAN Y, GAO P, et al. Disulfide-bond A oxidoreductase-like protein protects against ectopic fat deposition and lipid-related kidney damage in diabetic nephropathy[J]. Kidney Int, 2019, 95(4): 880-895. doi: 10.1016/j.kint.2018.10.038
[29]	HAN W, DU C, ZHU Y, et al. Targeting myocardial mitochondria-STING-polyamine axis prevents cardiac hypertrophy in chronic kidney disease[J]. JACC Basic Transl Sci, 2022, 7(8): 820-840. doi: 10.1016/j.jacbts.2022.03.006
[30]	BI X J, DU C H, WANG X M, et al. Mitochondrial damage-induced innate immune activation in vascular smooth muscle cells promotes chronic kidney disease-associated plaque vulnerability[J]. Adv Sci(Weinh), 2021, 8(5): 2002738. DOI: 10.1002/advs.202002738.
[31]	ABLASSER A, HUR S. Regulation of cGAS- and RLR-mediated immunity to nucleic acids[J]. Nat Immunol, 2020, 21(1): 17-29. doi: 10.1038/s41590-019-0556-1
[32]	SHU H B, WANG Y Y. Adding to the STING[J]. Immunity, 2014, 41(6): 871-873. doi: 10.1016/j.immuni.2014.12.002
[33]	TAKAHASHI M, LIO C J, CAMPEAU A, et al. The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-beta pathway[J]. Nat Immunol, 2021, 22(4): 485-496. doi: 10.1038/s41590-021-00896-3
[34]	SHI J Q, LIU C Q, LUO S N, et al. STING agonist and IDO inhibitor combination therapy inhibits tumor progression in murine models of colorectal cancer[J]. Cell Immunol, 2021, 366: 104384. DOI: 10.1016/j.cellimm.2021.104384.
[35]	BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. doi: 10.3322/caac.21492
[36]	WU Z, LIN Y, LIU L M, et al. Identification of cytosolic DNA sensor cGAS-STING as immune-related risk factor in renal carcinoma following pan-cancer analysis[J]. J Immunol Res, 2022, 2022: 7978042. DOI: 10.1155/2022/7978042.
[37]	AN X, ZHU Y, ZHENG T, et al. An analysis of the expression and association with immune cell infiltration of the cGAS/STING pathway in pan-cancer[J]. Mol Ther Nucleic Acids, 2019, 14: 80-89. doi: 10.1016/j.omtn.2018.11.003
[38]	王星月, 江蕾, 杨俊伟. 巨噬细胞能量代谢与肾脏疾病的研究进展[J]. 中华全科医学, 2020, 18(8): 1348-1352. doi: 10.16766/j.cnki.issn.1674-4152.001504 WANG X Y, JIANG L, YANG J W. The role of metabolism in macrophage in Kidney diseases[J]. Chinese Journal of General Practice, 2020, 18(8): 1348-1352. doi: 10.16766/j.cnki.issn.1674-4152.001504