miR-124/MCP-1 signaling pathway modulates the protective effect of itraconazole on acute kidney injury in a mouse model of disseminated candidiasis

Li,Xiao‑Yue; Zhang,Yu‑Qi; Xu,Gang; Li,Shao‑Hong; Li,Heng

doi:10.3892/ijmm.2018.3564

miR-124/MCP-1 signaling pathway modulates the protective effect of itraconazole on acute kidney injury in a mouse model of disseminated candidiasis

Authors:
- Xiao‑Yue Li
- Yu‑Qi Zhang
- Gang Xu
- Shao‑Hong Li
- Heng Li
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Affiliations: Department of Critical Care Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guanxi 541199, P.R. China, Department of Geriatrics, Guangzhou First People's Hospital, Guangzhou, Guangdong 510000, P.R. China, Department of Emergency, TungWah Affiliated Hospital of Sun Yat‑sen University, Dongguan, Guangdong 523220, P.R. China, Department of Cardiovascular Medicine, TungWah Affiliated Hospital of Sun Yat‑sen University, Dongguan, Guangdong 523220, P.R. China
Published online on: March 13, 2018 https://doi.org/10.3892/ijmm.2018.3564
Pages: 3468-3476

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Abstract

Previous studies have indicated that monocyte chemoattractant protein-1 (MCP‑1), also referred to as C‑C motif chemokine ligand 2, has a significant role in the pathogenesis of sepsis, however, how microRNAs (miRs) contribute to this process remains to be fully elucidated. In the present study, using a mouse model of disseminated candidiasis, the renoprotective effect of itraconazole (ITR) and adenovirus‑delivered miR‑124 was investigated. The mice were treated with ITR (50 mg/kg) or transfected with miR‑124 mimics via tail‑vein injection 7 days prior to Candida albicans infection. The survival outcome was monitored following candidiasis‑induced sepsis with ITR or miR‑124 mimics treatment. The levels of pro‑inflammatory cytokines, including tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β) and IL‑6, were determined using enzyme‑linked immunosorbent assays. The mRNA and protein levels were assayed using reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. The results showed that ITR and miR‑124 mimics improved the survival outcome in candidiasis‑induced septic mice. The findings also indicated a significant downregulation in the serum levels of TNF‑α, IL‑1β and IL‑6 in the septic mice treated with ITR or miR‑124 mimics. Of note, ITR treatment significantly increased the expression of miR‑124 and decreased the levels of MCP‑1 in the kidneys of the septic mice. It was also shown that the overexpression of miR‑124 reduced the expression of MCP‑1 and attenuated candidiasis‑induced acute kidney injury (AKI) in septic mice. Transfection with miR‑124 mimics was equivalent to ITR in reducing the excessive inflammatory response and renal lesions in septic mice. These results provided evidence supporting the use of miR‑124 mimics as a therapeutic approach for attenuating candidiasis-induced AKI.

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1	Leelahavanichkul A, Somparn P, Bootprapan T, Tu H, Tangtanatakul P, Nuengjumnong R, Worasilchai N, Tiranathanagul K, Eiam-ong S, Levine M, et al: High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse. Am J Physiol Regul Integr Comp Physiol. 309:R223–R234. 2015. View Article : Google Scholar : PubMed/NCBI
2	Pfaller MA and Diekema DJ: Epidemiology of invasive candidiasis: A persistent public health problem. Clin Microbiol Rev. 20:133–163. 2007. View Article : Google Scholar : PubMed/NCBI
3	Lionakis MS, Swamydas M, Fischer BG, Plantinga TS, Johnson MD, Jaeger M, Green NM, Masedunskas A, Weigert R, Mikelis C, et al: CX3CR1-dependent renal macrophage survival promotes Candida control and host survival. J Clin Invest. 123:5035–5051. 2013. View Article : Google Scholar : PubMed/NCBI
4	Spellberg B, Ibrahim AS, Edwards JE Jr and Filler SG: Mice with disseminated candidiasis die of progressive sepsis. J Infect Dis. 192:336–343. 2005. View Article : Google Scholar : PubMed/NCBI
5	Ngo LY, Kasahara S, Kumasaka DK, Knoblaugh SE, Jhingran A and Hohl TM: Inflammatory monocytes mediate early and organ-specific innate defense during systemic candidiasis. J Infect Dis. 209:109–119. 2014. View Article : Google Scholar
6	Navarathna DH, Stein EV, Lessey-Morillon EC, Nayak D, Martin-Manso G and Roberts DD: CD47 promotes protective innate and adaptive immunity in a mouse model of disseminated candidiasis. PLoS One. 10:e01282202015. View Article : Google Scholar : PubMed/NCBI
7	Lionakis MS, Fischer BG, Lim JK, Swamydas M, Wan W, Richard Lee CC, Cohen JI, Scheinberg P, Gao JL and Murphy PM: Chemokine receptor Ccr1 drives neutrophil-mediated kidney immunopathology and mortality in invasive candidiasis. PLoS Pathog. 8:e10028652012. View Article : Google Scholar : PubMed/NCBI
8	Castillo L, MacCallum DM, Brown AJ, Gow NA and Odds FC: Differential regulation of kidney and spleen cytokine responses in mice challenged with pathology-standardized doses of Candida albicans mannosylation mutants. Infect Immun. 79:146–152. 2011. View Article : Google Scholar :
9	Imbert F, Jardin M, Fernandez C, Gantier JC, Dromer F, Baron G, Mentre F, Van Beijsterveldt L, Singlas E and Gimenez F: Effect of efflux inhibition on brain uptake of itraconazole in mice infected with Cryptococcus neoformans. Drug Metab Dispos. 31:319–325. 2003. View Article : Google Scholar : PubMed/NCBI
10	Carrer DP, Samonis G, Droggiti DI, Tsaganos T, Pistiki A and Giamarellos-Bourboulis EJ: Intravenous itraconazole against experimental neutropenic Candida parapsilosis infection: Efficacy after suppression of bacterial translocation. J Infect Chemother. 19:1080–1086. 2013. View Article : Google Scholar : PubMed/NCBI
11	Sharifzadeh A, Khosravi AR, Shokri H and Tari PS: Synergistic anticandidal activity of menthol in combination with itraconazole and nystatin against clinical Candida glabrata and Candida krusei isolates. Microb Pathog. 107:390–396. 2017. View Article : Google Scholar : PubMed/NCBI
12	Inoue H, Iwasaki H, Abe S, Yamaguchi H and Ueda T: Modulation of the human interleukin-12p40 response by a triazole antifungal derivative, itraconazole. Scand J Infect Dis. 36:607–609. 2004. View Article : Google Scholar : PubMed/NCBI
13	Wark PA, Hensley MJ, Saltos N, Boyle MJ, Toneguzzi RC, Epid GD, Simpson JL, McElduff P and Gibson PG: Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: A randomized controlled trial. J Allergy Clin Immunol. 111:952–957. 2003. View Article : Google Scholar : PubMed/NCBI
14	Oliveira AH, de Oliveira GG, Carnevale Neto F, Portuondo DF, Batista-Duharte A and Carlos IZ: Anti-inflammatory activity of Vismia guianensis (Aubl.) Pers Extracts and antifungal activity against Sporothrix schenckii. J Ethnopharmacol. 195:266–274. 2017. View Article : Google Scholar
15	Friccius H, Pohla H, Adibzadeh M, Siegels-Hubenthal P, Schenk A and Pawelec G: The effects of the antifungal azoles itraconazole, fluconazole, ketoconazole and miconazole on cytokine gene expression in human lymphoid cells. Int J Immunopharmacol. 14:791–799. 1992. View Article : Google Scholar : PubMed/NCBI
16	Ohta K, Ishida Y, Fukui A, Nishi H, Naruse T, Takechi M and Kamata N: Itraconazole inhibits TNF-α-induced CXCL10 expression in oral fibroblasts. Oral Dis. 21:106–112. 2015. View Article : Google Scholar
17	Naranjo TW, Lopera DE, Diaz-Granados LR, Duque JJ, Restrepo A and Cano LE: Histopathologic and immunologic effects of the itraconazole treatment in a murine model of chronic pulmonary paracoccidioidomycosis. Microbes Infect. 12:1153–1162. 2010. View Article : Google Scholar : PubMed/NCBI
18	Liu J, Shi K, Chen M, Xu L, Hong J, Hu B, Yang X and Sun R: Elevated miR-155 expression induces immunosuppression via CD39(+) regulatory T-cells in sepsis patient. Int J Infect Dis. 40:135–141. 2015. View Article : Google Scholar : PubMed/NCBI
19	Pan S, Yang X, Jia Y, Li Y, Chen R, Wang M, Cai D and Zhao R: Intravenous injection of microvesicle-delivery miR-130b alleviates high-fat diet-induced obesity in C57BL/6 mice through translational repression of PPAR-γ. J Biomed Sci. 22:862015. View Article : Google Scholar
20	Ge QM, Huang CM, Zhu XY, Bian F and Pan SM: Differentially expressed miRNAs in sepsis-induced acute kidney injury target oxidative stress and mitochondrial dysfunction pathways. PLoS One. 12:e01732922017. View Article : Google Scholar : PubMed/NCBI
21	Monk CE, Hutvagner G and Arthur JS: Regulation of miRNA transcription in macrophages in response to Candida albicans. PLoS One. 5:e136692010. View Article : Google Scholar : PubMed/NCBI
22	Li XY, Zhang K, Jiang ZY and Cai LH: MiR-204/miR-211 downregulation contributes to candidemia-induced kidney injuries via derepression of Hmx1 expression. Life Sci. 102:139–144. 2014. View Article : Google Scholar : PubMed/NCBI
23	Venturini J, de Camargo MR, Felix MC, Vilani-Moreno FR and de Arruda MS: Influence of tumour condition on the macrophage activity in Candida albicans infection. Scand J Immunol. 70:10–17. 2009. View Article : Google Scholar : PubMed/NCBI
24	Fan HY, Qi D, Yu C, Zhao F, Liu T, Zhang ZK, Yang MY, Zhang LM, Chen DQ and Du Y: Paeonol protects endotoxin-induced acute kidney injury: potential mechanism of inhibiting TLR4-NF-κB signal pathway. Oncotarget. 7:39497–39510. 2016. View Article : Google Scholar : PubMed/NCBI
25	Xiao F, Huang Z, Li H, Yu J, Wang C, Chen S, Meng Q, Cheng Y, Gao X and Li J: Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes. 60:746–756. 2011. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
27	He J, Chen Y, Lin Y, Zhang W, Cai Y, Chen F, Liao Q, Yin Z, Wang Y, Tao S, et al: Association study of MCP-1 promoter polymorphisms with the susceptibility and progression of sepsis. PLoS One. 12:e01767812017. View Article : Google Scholar : PubMed/NCBI
28	Labbe K, Danialou G, Gvozdic D, Demoule A, Divangahi M, Boyd JH and Petrof BJ: Inhibition of monocyte chemoattractant protein-1 prevents diaphragmatic inflammation and maintains contractile function during endotoxemia. Crit Care. 14:R1872010. View Article : Google Scholar : PubMed/NCBI
29	Dorso L, Bigot-Corbel E, Abadie J, Diab M, Gouard S, Bruchertseifer F, Morgenstern A, Maurel C, Chérel M and Davodeau F: Long-term toxicity of 213Bi-labelled BSA in mice. PLoS One. 11:e01513302016. View Article : Google Scholar : PubMed/NCBI
30	Kluger N, Kataja J, Aho H, Ronn AM, Krohn K and Ranki A: Kidney involvement in autoimmune polyendocrinopath y-candidiasis-ectodermal dystrophy in a Finnish cohort. Nephrol Dial Transplant. 29:1750–1757. 2014. View Article : Google Scholar : PubMed/NCBI
31	Munshi R, Johnson A, Siew ED, Ikizler TA, Ware LB, Wurfel MM, Himmelfarb J and Zager RA: MCP-1 gene activation marks acute kidney injury. J Am Soc Nephro. 22:165–175. 2011. View Article : Google Scholar
32	Vianna HR, Soares CM, Silveira KD, Elmiro GS, Mendes PM, de Sousa Tavares M, Teixeira MM, Miranda DM, Simões E and Silva AC: Cytokines in chronic kidney disease: Potential link of MCP-1 and dyslipidemia in glomerular diseases. Pediatr Nephrol. 28:463–469. 2013. View Article : Google Scholar
33	Yu C, Qi D, Sun JF, Li P and Fan HY: Rhein prevents endotoxin-induced acute kidney injury by inhibiting NF-κB activities. Sci Rep. 5:118222015. View Article : Google Scholar
34	Chen H, Zhu J, Liu Y, Dong Z, Liu H, Liu Y, Zhou X, Liu F and Chen G: Lipopolysaccharide induces chronic kidney injury and fibrosis through activation of mTOR signaling in macrophages. Am J Nephrol. 42:305–317. 2015. View Article : Google Scholar : PubMed/NCBI
35	Wang D, Shi L, Xin W, Xu J, Xu J, Li Q, Xu Z, Wang J, Wang G, Yao W, et al: Activation of PPARγ inhibits pro-inflammatory cytokines production by upregulation of miR-124 in vitro and in vivo. Biochem Biophys Res Commun. 486:726–731. 2017. View Article : Google Scholar : PubMed/NCBI
36	Li X, Fan Q, Li J, Song J and Gu Y: MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma. Exp Cell Res. 351:100–108. 2017. View Article : Google Scholar : PubMed/NCBI
37	Dong N, Xu B, Shi H and Tang X: Baicalein inhibits amadori-glycated albumin-induced MCP-1 expression in retinal ganglion cells via a microRNA-124-dependent mechanism. Invest Ophthalmol Vis Sci. 56:5844–5853. 2015. View Article : Google Scholar : PubMed/NCBI
38	Wang D, Zhang H, Li M, Frid MG, Flockton AR, McKeon BA, Yeager ME, Fini MA, Morrell NW, Pullamsetti SS, et al: MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res. 114:67–78. 2014. View Article : Google Scholar :
39	Fischer A: Gene therapy: Repair and replace. Nature. 510:226–227. 2014. View Article : Google Scholar : PubMed/NCBI
40	Zhou Y, Song Y, Shaikh Z, Li H, Zhang H, Caudle Y, Zheng S, Yan H, Hu D, Stuart C and Yin D: MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2. Oncotarget. 8:47317–47329. 2017.PubMed/NCBI
41	Zheng D, Yu Y, Li M, Wang G, Chen R, Fan GC, Martin C, Xiong S and Peng T: Inhibition of microRNA 195 prevents apoptosis and multiple-organ injury in mouse models of sepsis. J Infect Dis. 213:1661–1670. 2016. View Article : Google Scholar :