Treatment with toll‑like receptor 2 inhibitor ortho‑vanillin alleviates lipopolysaccharide‑induced acute kidney injury in mice

Peng,Yuan; Liu,Long; Wang,Yongfang; Yao,Jianyin; Jin,Fang; Tao,Tao; Yuan,Hua; Shi,Lei; Lu,Shiqi

doi:10.3892/etm.2019.8157

Treatment with toll‑like receptor 2 inhibitor ortho‑vanillin alleviates lipopolysaccharide‑induced acute kidney injury in mice

Authors:
- Yuan Peng
- Long Liu
- Yongfang Wang
- Jianyin Yao
- Fang Jin
- Tao Tao
- Hua Yuan
- Lei Shi
- Shiqi Lu
View Affiliations

Affiliations: Department of Emergency, The First Affiliated Hospital of Soochow University, Soochow, Jiangsu 215006, P.R. China, Intensive Care Unit, The First People's Hospital of Kunshan Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
Published online on: October 31, 2019 https://doi.org/10.3892/etm.2019.8157
Pages: 4829-4837
Copyright: © Peng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Reducing inflammation is a promising approach for the prevention and treatment of septic acute kidney injury (AKI), since AKI is characterized by excessive inflammation in the kidney. Previous studies have demonstrated that toll‑like receptor 2 (TLR2) is overstimulated, which promotes inflammation by activating the NF‑κB signaling pathway, in a lipopolysaccharide (LPS)‑induced model of AKI mice. For the present study, it was hypothesized that TLR2 inhibition could reduce inflammation and consequently prevent septic AKI. Therefore, the potential renal protective effects of ortho‑vanillin (OV), an inhibitor of TLR2, were investigated in the present study in vitro and in vivo. In vitro treatment with OV on LPS‑stimulated mouse podocyte cell line MPC5 did not affect TLR2 expression but interrupted the interaction between TLR2 and its downstream adaptor MyD88, resulting in the reduction of inflammatory cytokines IL‑6 and TNF‑α expression. In vivo OV treatment in an LPS‑challenged mouse model effectively alleviated LPS‑induced kidney injury as indicated by histology analysis and the significantly reduced blood urea nitrogen and serum creatinine levels. Additionally, inflammatory cytokines TNF‑α, IL‑6 and IL‑1β expression were also significantly reduced in mice with OV treatment. Signaling pathway analysis further demonstrated that OV treatment did not affect the expression of TLR2 and p65 but suppressed p65 phosphorylation. Taken together, data from the present study demonstrated that OV was effective in protecting renal function against LPS‑induced AKI through the inhibition of TLR2/NF‑κB signaling and subsequent inflammatory cytokine production. These findings indicated that OV or targeting TLR2 signaling in general, represents a novel therapeutic approach for use in the prevention and treatment of AKI.

View Figures

View References

1	Mehta RL, Cerda J, Burdmann EA, Tonelli M, García-García G, Jha V, Susantitaphong P, Rocco M, Vanholder R, Sever MS, et al: International society of nephrology's 0 by 25 initiative for acute kidney injury (zero preventable deaths by 2025): A human rights case for nephrology. Lancet. 385:2616–2643. 2015. View Article : Google Scholar : PubMed/NCBI
2	Rewa O and Bagshaw SM: Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol. 10:193–207. 2014. View Article : Google Scholar : PubMed/NCBI
3	Yang L, Xing G, Wang L, Wu Y, Li S, Xu G, He Q, Chen J, Chen M, Liu X, et al: Acute kidney injury in China: A cross-sectional survey. Lancet. 386:1465–1471. 2015. View Article : Google Scholar : PubMed/NCBI
4	Jha V and Parameswaran S: Community-acquired acute kidney injury in tropical countries. Nat Rev Nephrol. 9:278–290. 2013. View Article : Google Scholar : PubMed/NCBI
5	Cerda J, Bagga A, Kher V and Chakravarthi RM: The contrasting characteristics of acute kidney injury in developed and developing countries. Nat Clin Pract Nephrol. 4:138–153. 2008. View Article : Google Scholar : PubMed/NCBI
6	Chawla LS, Amdur RL, Amodeo S, Kimmel PL and Palant CE: The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int. 79:1361–1369. 2011. View Article : Google Scholar : PubMed/NCBI
7	Zuk A and Bonventre JV: Acute kidney injury. Annu Rev Med. 67:293–307. 2016. View Article : Google Scholar : PubMed/NCBI
8	Makris K and Spanou L: Acute kidney injury: Definition, pathophysiology and clinical phenotypes. Clin Biochem Rev. 37:85–98. 2016.PubMed/NCBI
9	Friedewald JJ and Rabb H: Inflammatory cells in ischemic acute renal failure. Kidney Int. 66:486–491. 2004. View Article : Google Scholar : PubMed/NCBI
10	Bonventre JV and Zuk A: Ischemic acute renal failure: An inflammatory disease? Kidney Int. 66:480–485. 2004. View Article : Google Scholar : PubMed/NCBI
11	Hu L, Chen C, Zhang J, Wu K, Zhang X, Liu H and Hou J: IL-35 pretreatment alleviates lipopolysaccharide-induced acute kidney injury in mice by inhibiting NF-κB activation. Inflammation. 40:1393–1400. 2017. View Article : Google Scholar : PubMed/NCBI
12	Zuk A, Gershenovich M, Ivanova Y, MacFarland RT, Fricker SP and Ledbetter S: CXCR₄ antagonism as a therapeutic approach to prevent acute kidney injury. Am J Physiol Renal Physiol. 307:F783–F797. 2014. View Article : Google Scholar : PubMed/NCBI
13	Gigliotti JC, Huang L, Ye H, Bajwa A, Chattrabhuti K, Lee S, Klibanov AL, Kalantari K, Rosin DL and Okusa MD: Ultrasound prevents renal ischemia-reperfusion injury by stimulating the splenic cholinergic anti-inflammatory pathway. J Am Soc Nephrol. 24:1451–1460. 2013. View Article : Google Scholar : PubMed/NCBI
14	Castoldi A, Braga TT, Correa-Costa M, Aguiar CF, Bassi ÊJ, Correa-Silva R, Elias RM, Salvador F, Moraes-Vieira PM, Cenedeze MA, et al: TLR2, TLR4 and the MYD88 signaling pathway are crucial for neutrophil migration in acute kidney injury induced by sepsis. PLoS One. 7:e375842012. View Article : Google Scholar : PubMed/NCBI
15	Gluba A, Banach M, Hannam S, Mikhailidis DP, Sakowicz A and Rysz J: The role of Toll-like receptors in renal diseases. Nat Rev Nephrol. 6:224–235. 2010. View Article : Google Scholar : PubMed/NCBI
16	Alves-Filho JC, Freitas A, Souto FO, Spiller F, Paula-Neto H, Silva JS, Gazzinelli RT, Teixeira MM, Ferreira SH and Cunha FQ: Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis. Proc Natl Acad Sci USA. 106:4018–4023. 2009. View Article : Google Scholar : PubMed/NCBI
17	Peng Y, Zhang X, Wang Y, Li S, Wang J and Liu L: Overexpression of toll-like receptor 2 in glomerular endothelial cells and podocytes in septic acute kidney injury mouse model. Ren Fail. 37:694–698. 2015. View Article : Google Scholar : PubMed/NCBI
18	Peng Y, Zhang X, Wang Y, Yuan H, Zhang S and Liu L: Toll like receptor 2 induces kidney inflammation via MyD88/NF-κB signaling pathway. Int J Clin Exp Med. 11:3494–3503. 2018.
19	Chen Y, Lin L, Tao X, Song Y, Cui J and Wan J: The role of podocyte damage in the etiology of ischemia-reperfusion acute kidney injury and post-injury fibrosis. BMC Nephrol. 20:1062019. View Article : Google Scholar : PubMed/NCBI
20	Perkin WH and Robinson R: CCXXII. - Some derivatives of ortho-vanillin. J Chem Soc Transactions. 105:2376–2392. 1914. View Article : Google Scholar
21	Mistry P, Laird MH, Schwarz RS, Greene S, Dyson T, Snyder GA, Xiao TS, Chauhan J, Fletcher S, Toshchakov VY, et al: Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain. Proc Natl Acad Sci USA. 112:5455–5460. 2015. View Article : Google Scholar : PubMed/NCBI
22	Rueden CT, Schindelin J, Hiner MC, DeZonia BE, Walter AE, Arena ET and Eliceiri KW: ImageJ2: ImageJ for the next generation of scientific image data. BMC Bioinformatics. 18:5292017. View Article : Google Scholar : PubMed/NCBI
23	Hu L, Chen C, Zhang J, Wu K, Zhang X, Liu H and Hou J: IL-35 Pre-treatment alleviates lipopolysaccharide-induced acute kidney injury in mice by inhibiting NF-κB activation. Inflammation. 40:1393–1400. 2017. View Article : Google Scholar : PubMed/NCBI
24	Liu Y, Yin H, Zhao M and Lu Q: TLR2 and TLR4 in autoimmune diseases: A comprehensive review. Clin Rev Allergy Immunol. 47:136–147. 2014. View Article : Google Scholar : PubMed/NCBI
25	Chawla LS, Seneff MG, Nelson DR, Williams M, Levy H, Kimmel PL and Macias WL: Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis. Clin J Am Soc Nephrol. 2:22–30. 2007. View Article : Google Scholar : PubMed/NCBI
26	Paladino JD, Hotchkiss JR and Rabb H: Acute kidney injury and lung dysfunction: A paradigm for remote organ effects of kidney disease? Microvasc Res. 77:8–12. 2009. View Article : Google Scholar : PubMed/NCBI
27	Xu C, Chang A, Hack BK, Eadon MT, Alper SL and Cunningham PN: TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis. Kidney Int. 85:72–81. 2014. View Article : Google Scholar : PubMed/NCBI
28	Ajuwon KM and Spurlock ME: Adiponectin inhibits LPS-induced NF-kappaB activation and IL-6 production and increases PPARgamma2 expression in adipocytes. Am J Physiol Regul Integr Comp Physiol. 288:R1220–F1225. 2005. View Article : Google Scholar : PubMed/NCBI
29	Cascinu S, Scartozzi M, Carbonari G, Pierantoni C, Verdecchia L, Mariani C, Squadroni M, Antognoli S, Silva RR, Giampieri R and Berardi R: COX-2 and NF-κB overexpression is common in pancreatic cancer but does not predict for COX-2 inhibitors activity in combination with gemcitabine and oxaliplatin. Am J Clin Oncol. 30:526–530. 2007. View Article : Google Scholar : PubMed/NCBI
30	Zarjou A and Agarwal A: Sepsis and acute kidney injury. J Am Soc Nephrol. 22:999–1006. 2011. View Article : Google Scholar : PubMed/NCBI
31	Grigoryev DN, Liu M, Hassoun HT, Cheadle C, Barnes KC and Rabb H: The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol. 19:547–558. 2008. View Article : Google Scholar : PubMed/NCBI
32	Ye HY, Jin J, Jin LW, Chen Y, Zhou ZH and Li ZY: Chlorogenic acid attenuates lipopolysaccharide-induced acute kidney injury by inhibiting TLR4/NF-κB signal pathway. Inflammation. 40:523–529. 2017. View Article : Google Scholar : PubMed/NCBI
33	Dorak MT: Basic immunology: Functions and disorders of the immune system. Am J Epidemiol. 155:185–186. 2012. View Article : Google Scholar
34	Gustafson GL and Rhodes MJ: A rationale for the prophylactic use of monophosphoryl lipid A in sepsis and septic shock. Biochem Biophys Res Commun. 182:269–275. 1992. View Article : Google Scholar : PubMed/NCBI
35	Poelstra K, Bakker WW, Klok PA, Hardonk MJ and Meijer DK: A physiologic function for alkaline phosphatase: Endotoxin detoxification. Lab Invest. 76:319–327. 1997.PubMed/NCBI
36	Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C and Payen D: Cytokine cascade in sepsis. Scand J Infect Dis. 35:535–544. 2003. View Article : Google Scholar : PubMed/NCBI
37	Cunningham PN, Ying W, Guo R, Gang H and Quigg RJ: Role of toll-like receptor 4 in endotoxin-induced acute renal failure. J Immunol. 172:2629–2635. 2004. View Article : Google Scholar : PubMed/NCBI
38	Fiedler VB, Loof I, Sander E, Voehringer V, Galanos C and Fournel MA: Monoclonal antibody to tumor necrosis factor-alpha prevents lethal endotoxin sepsis in adult rhesus monkeys. J Lab Clin Med. 120:574–588. 1992.PubMed/NCBI
39	Pasquet V, Perwuelz A, Behary N and Isaad J: Vanillin, a potential carrier for low temperature dyeing of polyester fabrics. J Cleaner Product. 43:20–26. 2013. View Article : Google Scholar
40	Shmuel-Galia L, Aychek T, Fink A, Porat Z, Zarmi B, Bernshtein B, Brenner O, Jung S and Shai Y: Neutralization of pro-inflammatory monocytes by targeting TLR2 dimerization ameliorates colitis. EMBO J. 35:685–698. 2016. View Article : Google Scholar : PubMed/NCBI
41	Landais I, Pelton C, Streblow D, DeFilippis V, McWeeney S and Nelson JA: Human Cytomegalovirus miR-UL112-3p targets TLR2 and modulates the TLR2/IRAK1/NFκB signaling pathway. PLoS Pathog. 11:e10048812015. View Article : Google Scholar : PubMed/NCBI
42	Koymans KJ, Feitsma LJ, Brondijk TH, Aerts PC, Lukkien E, Lössl P, van Kessel KP, de Haas CJ, van Strijp JA and Huizinga EG: Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3). Proc Natl Acad Sci USA. 112:11018–11023. 2015. View Article : Google Scholar : PubMed/NCBI