WIN55212-2通过调控AKT/mTOR/PFKFB3信号通路减轻脓毒症小鼠急性肾损伤

董旭鹏; 段倩雯; 马源; 刘澈; 龚禹; 马玉清

doi:10.16016/j.2097-0927.202307071

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WIN55212-2通过调控AKT/mTOR/PFKFB3信号通路减轻脓毒症小鼠急性肾损伤

基础医学 | 更新时间：2026-01-09

- WIN55212-2通过调控AKT/mTOR/PFKFB3信号通路减轻脓毒症小鼠急性肾损伤
- WIN55212-2 alleviates acute kidney injury in septic mice by regulating the AKT/mTOR/PFKFB3 signaling pathway
- 陆军军医大学学报 2024年46卷第10期页码：1100-1106
- 作者机构：
  
  1.730000 兰州，兰州大学：第一临床医学院
  2.730000 兰州，兰州大学：第一医院麻醉科
- 作者简介：
  
  [马玉清，E-mail: myq2392466@163.com MA Yuqing, E-mail: myq2392466@163.com
- 基金信息：
  
  甘肃省自然科学基金(21JRIRA077)
- DOI：10.16016/j.2097-0927.202307071
  中图分类号： R631.2;R692;R977.9
- 收稿：2023-07-17，
  
  修回：2023-09-25，
  
  纸质出版：2024-05-30
- 稿件说明：
移动端阅览
董旭鹏, 段倩雯, 马源, 等. WIN55212-2通过调控AKT/mTOR/PFKFB3信号通路减轻脓毒症小鼠急性肾损伤[J]. 陆军军医大学学报, 2024,46(10):1100-1106.

Xupeng DONG, Qianwen DUAN, Yuan MA, et al. WIN55212-2 alleviates acute kidney injury in septic mice by regulating the AKT/mTOR/PFKFB3 signaling pathway[J]. Journal of Army Medical University, 2024, 46(10): 1100-1106.
董旭鹏, 段倩雯, 马源, 等. WIN55212-2通过调控AKT/mTOR/PFKFB3信号通路减轻脓毒症小鼠急性肾损伤[J]. 陆军军医大学学报, 2024,46(10):1100-1106. DOI： 10.16016/j.2097-0927.202307071.

Xupeng DONG, Qianwen DUAN, Yuan MA, et al. WIN55212-2 alleviates acute kidney injury in septic mice by regulating the AKT/mTOR/PFKFB3 signaling pathway[J]. Journal of Army Medical University, 2024, 46(10): 1100-1106. DOI： 10.16016/j.2097-0927.202307071.

摘要

目的

探讨大麻素受体激动剂WIN55212-2(WIN)对脓毒症小鼠急性肾损伤(acute kidney injury，AKI)的影响及其作用机制。

方法

24只雄性健康小鼠分为4组(

=6): 对照组(Control组)、脓毒症组(LPS组)、脓毒症+WIN55212-2组(LPS+WIN组)和脓毒症+WIN55212-2+mTOR激活剂MHY1485组(LPS+WIN+MHY组)。采用腹腔注射脂多糖(lipopolysaccharide，LPS)的方法构建脓毒症模型，造模24 h后取材，ELISA测定肾脏组织IL-1β、IL-18和乳酸脱氢酶A(lactate dehydrogenase A，LDHA)的含量以及血清Scr、肾损伤分子-1(kidney injury molecule-1，KIM-1)和乳酸

的含量；HE染色观察肾脏组织病理改变并进行Paller评分，Western blot检测肾脏组织p-AKT、p-mTOR及6-磷酸果糖激酶-2/果糖-2

6-二磷酸酶3(6-phosphofructo-2-kinase/fructose-2

6-biphosphatase 3，PFKFB3)的表达。

结果

与Control组相比，LPS组HE染色显示肾脏组织受损，Paller评分升高(

0.05)，血清乳酸、Scr、KIM-1含量升高(

0.05)，肾脏组织LDHA、IL-1β、IL-18含量上调(

0.05)，肾脏组织p-AKT、p-mTOR、PFKFB3表达增加(

0.05)。与LPS组相比，LPS+WIN组肾脏组织病理损伤减轻，Paller评分降低(

0.05)，乳酸、Scr、KIM-1的含量降低(

0.05)，LDHA、IL-1β、IL-18含量下调(

0.05)，p-AKT、p-mTOR、PFKFB3表达减少(

0.05)。与LPS+WIN组相比，LPS+WIN+MHY组Paller评分升高(

0.05)，乳酸、Scr、KIM-1的含量升高(

0.05)，LDHA、IL-1β、IL-18含量上调(

0.05)，p-AKT、p-mTOR、PFKFB3表达增加(

0.05)。

结论

WIN可以减轻脓毒症AKI，其机制可能是通过抑制AKT/mTOR/PFKFB3信号通路，降低肾脏组织糖酵解水平，减轻炎症反应。

Abstract

Objective

To investigate the effects of cannabinoid receptor agonist

WIN55212-2 (WIN)

on acute kidney injury (AKI) in mice with sepsis and its underlying mechanism.

Methods

Twenty-four healthy male mice were divided into (

=6): Control group

sepsis group (LPS group)

sepsis+WIN55212-2 group (LPS+WIN group) and sepsis+WIN55212-2+mTOR activator MHY1485 group (LPS+WIN+MHY group). The sepsis model was constructed by intraperitoneal injection of LPS. After the tissue and blood samples were harvested in 24 h after modeling

ELISA was used to determine the contents of IL-1β

IL-18 and lactate dehydrogenase A (LDHA) in the renal tissues

as well as Scr

kidney injury molecule-1 (KIM-1) and lactic acid (LA) in the serum. HE staining was employed to observe the pathological changes of kidney tissue and Paller score was calculated. The expression of p-AKT

p-mTOR and 6-phosphofructokinase-2/fructose-2

6-biphosphatase 3 (PFKF

B3) in the renal tissues was detected by Western blotting.

Results

Compared with the Control group

the LPS group had obvious kidney tissue damage

increased Paller score (

0.05)

increased serum contents of lactic acid

Scr and KIM-1 (

0.05)

up-regulated contents of LDHA

IL-1β and IL-18 in the renal tissues (

0.05)

and elevated expression levels of p-AKT

p-mTOR and PFKFB3 in the renal tissues (

0.05). Milder pathological injury in kidney tissue

decreased Paller score (

0.05)

reduced contents of lactic acid

Scr and KIM-1 (

0.05)

decreased contents of LDHA

IL-1β and IL-18 (

0.05)

and lower expression of p-AKT

p-mTOR and PFKFB3 were observed in the LPS+WIN group than the LPS group (

0.05). The LPS+WIN+MHY group had notably higher Paller score (

0.05)

raised contents of lactic acid

Scr and KIM-1 (

0.05)

increased contents of LDHA

IL-1β and IL-18 (

0.05)

and up-regulated expression of p-AKT

p-mTOR and PFKFB3 (

0.05) when compared with the LPS+WIN group.

Conclusion

WIN can alleviate AKI in sepsis

and it may reduce the level of glycolysis in renal tissue

and alleviate inflammation through inhibiting AKT/mTOR/PFKFB3 signaling pathway.

关键词

Keywords

references

FERNANDO S M, ROCHWERG B, SEELY A J E. Clinical implications of the third international consensus definitions for sepsis and septic shock (Sepsis-3)[J]. CMAJ, 2018, 190(36): E1058-E1059. DOI: 10.1503/cmaj.170149.

KUWABARA S, GOGGINS E, OKUSA M D. The pathophysiology of sepsis-associated AKI[J]. Clin J Am Soc Nephrol, 2022, 17(7): 1050-1069. DOI: 10.2215/CJN.00850122.

MANRIQUE-CABALLERO C L, DEL RIO-PERTUZ G, GOMEZ H. Sepsis-associated acute kidney injury[J]. Crit Care Clin, 2021, 37(2): 279-301. DOI: 10.1016/j.ccc.2020.11.010.

POSTON J T, KOYNER J L. Sepsis associated acute kidney injury[J]. BMJ, 2019: k4891. DOI: 10.1136/bmj.k4891.

KALANTARI K, ROSNER M H. Recent advances in the pharmacological management of sepsis-associated acute kidney injury[J]. Expert Rev Clin Pharmacol, 2021, 14(11): 1401-1411. DOI: 10.1080/17512433.2021.1978287.

SINGBARTL K, FORMECK C L, KELLUM J A. Kidney-immune system crosstalk in AKI[J]. Semin Nephrol, 2019, 39(1): 96-106. DOI: 10.1016/j.semnephrol.2018.10.007.

SUN L Z, YANG X F, YUAN Z Y, et al . Metabolic reprogramming in immune response and tissue inflammation[J ] . Arterioscler Thromb Vasc Biol, 2020, 40(9): 1990-2001. DOI: 10.1161/atvbaha.120.314037.

TAN C Y, GU J, LI T, et al . Inhibition of aerobic glycolysis alleviates sepsis-induced acute kidney injury by promoting lactate/Sirtuin 3/AMPK-regulated autophagy[J ] . Int J Mol Med, 2021, 47(3): 19. DOI: 10.3892/ijmm.2021.4852.

LIAO S, LIANG L, YUE C X, et al . CD38 is involved in cell energy metabolism via activating the PI3K/AKT/mTOR signaling pathway in cervical cancer cells[J ] . Int J Oncol, 2020, 57(1): 338-354. DOI: 10.3892/ijo.2020.5040..

ZHANG T, ZHANG Y G, YANG Z H, et al . Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 macrophages through PI3K/Akt/mTOR signaling pathway[J ] . Pathog Glob Health, 2023, 117(4): 409-416. DOI: 10.1080/20477724.2022.2104055..

HU X T, XU Q Y, WAN H X, et al . PI3K-Akt-mTOR/PFKFB 3 pathway mediated lung fibroblast aerobic glycolysis and collagen synthesis in lipopolysaccharide-induced pulmonary fibrosis[J ] . Lab Invest, 2020, 100(6): 801-811. DOI: 10.1038/s41374-020-0404-9..

WILHELMSEN K, KHAKPOUR S, TRAN A, et al . The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55, 212-2 abate the inflammatory activation of human endothelial cells[J ] . J Biol Chem, 2014, 289(19): 13079-13100. DOI: 10.1074/jbc.M113.536953.

HE Q A, YIN J, ZOU B S, et al . WIN55212-2 alleviates acute lung injury by inhibiting macrophage glycolysis through the miR-29b-3p/FOXO3/PF KFB 3 axis[J ] . Mol Immunol, 2022, 149: 119-128. DOI: 10.1016/j.molimm.2022.06.005..

LIU L Q, YAN M J, YANGR, et al . Adiponectin attenuates lipopolysaccharide-induced apoptosis by regulating the Cx43/PI3K/AKT pathway[J ] . Front Pharmacol, 2021, 12: 644225. DOI: 10.3389/fphar.2021.644225.

ZHOU J L, YAO W, LI C Y, et al . Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1α in mouse granulosa cells[J ] . Cell Death Dis, 2017, 8(8):e3001. DOI: 10.1038/cddis.2017.371..

PALLER M S, HOIDAL J R, FERRIS T F. Oxygen free radicals in ischemic acute renal failure in the rat[J]. J Clin Invest, 1984, 74(4): 1156-1164. DOI: 10.1172/JCI111524.

SU S H, WU Y F, LIN Q, et al . Cannabinoid receptor agonist WIN55, 212-2 and fatty acid amide hydrolase inhibitor URB597 ameliorate neuroinflammatory responses in chronic cerebral hypoperfusion model by blocking NF-κB pathways[J ] . Naunyn Schmiedebergs Arch Pharmacol, 2017, 390(12): 1189-1200. DOI: 10.1007/s00210-017-1417-9.

PÉREZ-DIEGO M, ANGELINA A, MARTÍN-CRUZ L, et al . Cannabinoid WIN55, 212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation[J ] . Front Immunol, 2023, 14: 1147520. DOI: 10.3389/fimmu.2023.1147520.

FIELDS J A, SWINTON M K, MONTILLA-PEREZ P, et al . The cannabinoid receptor agonist, WIN-55212-2, suppresses the activation of proinflammatory genes induced by interleukin 1 beta in human astrocytes[J ] . Cannabis Cannabinoid Res, 2022, 7(1): 78-92. DOI: 10.1089/can.2020.0128.

MOLEDINA D G, PARIKH C R. Phenotyping of acute kidney injury: beyond serum creatinine[J]. Semin Nephrol, 2018, 38(1): 3-11. DOI: 10.1016/j.semnephrol.2017.09.002.

DIAO H Y, ZHU W, LIU J, et al . Salvianolic acid A improves rat kidney injury by regulating MAPKs and TGF-β1/smads signaling pathways[J ] . Molecules, 2023, 28(8): 3630. DOI: 10.3390/molecules28083630.

ZHENG Z B, MA H, ZHANG X, et al . Enhanced glycolytic metabolism contributes to cardiac dysfunction in polymicrobial Sepsis [J ] . J Infect Dis, 2017, 215(9): 1396-1406. DOI: 10.1093/infdis/jix138..

LIU W Z, LIU T Y, ZHENG Y J, et al . Me tabolic reprogramming and its regulatory mechanism in sepsis-mediated inflammation[J ] . J Inflamm Res, 2023, 16: 1195-1207. DOI: 10.2147/JIR.S403778.

WANG L, WANG D G, ZHANG T L, et al . The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome[J ] . Front Immunol, 2023, 14: 1117548. DOI: 10.3389/fimmu.2023.1117548.

POUYSSÉGUR J, MARCHIQ I, PARKS S K, et al . 'Warburg effect' controls tumor growth, bacterial, viral infections and immunity—Genetic deconstruction and therapeutic perspectives[J ] . Semin Cancer Biol, 2022, 86 (Pt 2): 334-346. DOI: 10.1016/j.semcancer.2022.07.004.

BAO Y F, ZHOU L, DAI D Q, et al . Discover potential inhibitors for PFKFB 3 using 3D-QSAR, virtual screening, molecular docking and molecular dynamics simulation[J ] . J Recept Signal Transduct, 2018, 38(5/6): 413-431. DOI: 10.1080/10799893.2018.1564150..

LUO P, ZHANG Q, ZHONG T Y, et al . Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect[J ] . Mil Med Res, 2022, 9(1): 22. DOI: 10.1186/s40779-022-00381-4.

CAI Y, GAO Q, MENG J H, et al . Puerarin suppresses glycolysis and increases cisplatin chemosensitivity in oral squamous cell carcinoma via FBXW7/mTOR signaling[J ] . Nutr Cancer, 2023, 75(3): 1028-1037. DOI: 10.1080/01635581.2023.2168023..

CHOU W C, RAMPANELLI E, LI X, et al . Impact of intracellular innate immune receptors on immunometabolism[J ] . Cell Mol Immunol, 2022, 19(3): 337-351. DOI: 10.1038/s41423-021-00780-y.

ABDEL-WAHAB A F, MAHMOUD W, AL-HARIZY R M.Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy[J]. Pharmacol Res, 2019, 150: 104511. DOI: 10.1016/j.phrs.2019.104511.

FENG Y H, WU L S. mTOR up-regulation of PFKFB 3 is essential for acute myeloid leukemia cell survival[J ] . Biochem Biophys Res Commun, 2017, 483(2): 897-903. DOI: 10.1016/j.bbrc.2017.01.031.

ANGELINA A, PÉREZ-DIEGO M, LÓPEZ-ABENTE J, et al . Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming[J ] . Mucosal Immunol, 2022, 15(1): 96-108. DOI: 10.1038/s41385-021-00455-x..

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