Inhibition of Semaphorin-3a Suppresses Lipopolysaccharide-induced Acute Kidney Injury

Overview

Journal J Mol Med (Berl)

Specialty General Medicine

Date 2018 Jun 18

PMID 29909462

Citations 17

Authors

Xiaofang Tian

Hua Gan

Yizhou Zeng

Hongfei Zhao

Rong Tang

Yunfeng Xia

Affiliations

Soon will be listed here.

Abstract

Semaphorin-3a (Sema3A), a soluble axon guidance cue, appears to play an important role in the development of acute kidney injury (AKI) and has been regarded as an early diagnostic marker to evaluate the progression of AKI. However, the role of Sema3A in sepsis-associated AKI remains unknown. In this study, lipopolysaccharide (LPS) was used to simulate sepsis-associated AKI and the role of Sema3A in LPS-induced AKI was investigated in vivo and in vitro. In our in vivo study, Sema3A was found in tubular epithelial cells (TECs), which presented a higher level after LPS treatment. Meanwhile, the results of our in vitro experiment showed that Sema3A was also elevated in NRK-52E cells treated by LPS. Notably, inhibition of Sema3A by (-)-epigallocatechin-3-gallate (EGCG) could significantly reduce kidney inflammation and apoptosis in mice. Likewise, EGCG intervention also ameliorated the inflammation and apoptosis of cells in vitro. Furthermore, our research also found that the Rac1/NF-κB p65 and JNK pathways were possibly involved in the Sema3A-mediated inflammation and apoptosis of TECs, respectively. Our findings suggest that Sema3A play a pathogenic role by promoting inflammation and apoptosis of TECs in LPS-induced AKI. It might serve as a useful treatment target in ameliorating sepsis-associated AKI. KEY MESSAGES: Sema3A is upregulated in LPS-induced AKI. Inhibition of Sema3A attenuates inflammation and apoptosis of TECs in LPS-induced AKI. Sema3A enhances the LPS-induced inflammation of TECs through the Rac1/NF-κB p65 pathway. Sema3A exacerbates the LPS-induced apoptosis of TECs through the JNK pathway.

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References

Xu C, Chang A, Hack B, Eadon M, Alper S, Cunningham P . TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis. Kidney Int. 2013; 85(1):72-81. PMC: 3834073. DOI: 10.1038/ki.2013.286. View

Godin M, Murray P, Mehta R . Clinical approach to the patient with AKI and sepsis. Semin Nephrol. 2015; 35(1):12-22. PMC: 5617729. DOI: 10.1016/j.semnephrol.2015.01.003. View

Chen Y, Du Y, Li Y, Wang X, Gao P, Yang G . Panaxadiol Saponin and Dexamethasone Improve Renal Function in Lipopolysaccharide-Induced Mouse Model of Acute Kidney Injury. PLoS One. 2015; 10(7):e0134653. PMC: 4521715. DOI: 10.1371/journal.pone.0134653. View

Doi K, Noiri E, Nangaku M, Yahagi N, Jayakumar C, Ramesh G . Repulsive guidance cue semaphorin 3A in urine predicts the progression of acute kidney injury in adult patients from a mixed intensive care unit. Nephrol Dial Transplant. 2013; 29(1):73-80. PMC: 3888311. DOI: 10.1093/ndt/gft414. View

Guttmann-Raviv N, Shraga-Heled N, Varshavsky A, Guimaraes-Sternberg C, Kessler O, Neufeld G . Semaphorin-3A and semaphorin-3F work together to repel endothelial cells and to inhibit their survival by induction of apoptosis. J Biol Chem. 2007; 282(36):26294-305. DOI: 10.1074/jbc.M609711200. View

Moretti S, Procopio A, Lazzarini R, Rippo M, Testa R, Marra M . Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts. Blood. 2007; 111(4):2290-9. DOI: 10.1182/blood-2007-06-096529. View

Kim T, Yoon J, Cho H, Lee W, Kim J, Song Y . Downregulation of lipopolysaccharide response in Drosophila by negative crosstalk between the AP1 and NF-kappaB signaling modules. Nat Immunol. 2005; 6(2):211-8. DOI: 10.1038/ni1159. View

de Wit J, Verhaagen J . Role of semaphorins in the adult nervous system. Prog Neurobiol. 2003; 71(2-3):249-67. DOI: 10.1016/j.pneurobio.2003.06.001. View

Kang Y, Falk M, Bentley T, Lee C . Distribution and role of lipopolysaccharide in the pathogenesis of acute renal proximal tubule injury. Shock. 1995; 4(6):441-9. View

10.

Karkar A, Rees A . Influence of endotoxin contamination on anti-GBM antibody induced glomerular injury in rats. Kidney Int. 1998; 52(6):1579-83. DOI: 10.1038/ki.1997.488. View

11.

Ikezumi Y, Hurst L, Atkins R, Nikolic-Paterson D . Macrophage-mediated renal injury is dependent on signaling via the JNK pathway. J Am Soc Nephrol. 2004; 15(7):1775-84. DOI: 10.1097/01.asn.0000131272.06958.de. View

12.

Schrier R, Wang W . Acute renal failure and sepsis. N Engl J Med. 2004; 351(2):159-69. DOI: 10.1056/NEJMra032401. View

13.

Bao H, Ge Y, Peng A, Gong R . Fine-tuning of NFκB by glycogen synthase kinase 3β directs the fate of glomerular podocytes upon injury. Kidney Int. 2015; 87(6):1176-90. PMC: 4449834. DOI: 10.1038/ki.2014.428. View

14.

Guo C, Wang S, Xu S, Wang J, Song G . SP600125 reduces lipopolysaccharide-induced apoptosis and restores the early-stage differentiation of osteoblasts inhibited by LPS through the MAPK pathway in MC3T3-E1 cells. Int J Mol Med. 2015; 35(5):1427-34. DOI: 10.3892/ijmm.2015.2130. View

15.

Lerman O, Ben-Zvi A, Yagil Z, Behar O . Semaphorin3A accelerates neuronal polarity in vitro and in its absence the orientation of DRG neuronal polarity in vivo is distorted. Mol Cell Neurosci. 2007; 36(2):222-34. DOI: 10.1016/j.mcn.2007.07.003. View

16.

Turner L, Nicholls S, Hall A . The activity of the plexin-A1 receptor is regulated by Rac. J Biol Chem. 2004; 279(32):33199-205. DOI: 10.1074/jbc.M402943200. View

17.

Endo Y, Kanbayashi H, Hara M . Experimental immunoglobulin A nephropathy induced by gram-negative bacteria. Nephron. 1993; 65(2):196-205. DOI: 10.1159/000187474. View

18.

Guo J, Wang L, Wang L, Qian S, Zhang D, Fang J . Berberine Protects Human Umbilical Vein Endothelial Cells against LPS-Induced Apoptosis by Blocking JNK-Mediated Signaling. Evid Based Complement Alternat Med. 2016; 2016:6983956. PMC: 4961818. DOI: 10.1155/2016/6983956. View

19.

Wen H, Lei Y, Eun S, Ting J . Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm. J Exp Med. 2010; 207(13):2943-57. PMC: 3005237. DOI: 10.1084/jem.20101138. View

20.

Kanellis J, Ma F, Kandane-Rathnayake R, Dowling J, Polkinghorne K, Bennett B . JNK signalling in human and experimental renal ischaemia/reperfusion injury. Nephrol Dial Transplant. 2010; 25(9):2898-908. DOI: 10.1093/ndt/gfq147. View