Green propolis extract attenuates acute kidney injury and lung injury in a rat model of sepsis
Marcelo Augusto Duarte Silveira, José Manuel Condor Capcha, Talita Rojas Sanches, Roberto de Sousa Moreira, Margot S Garnica, Maria Heloisa Shimizu, Andresa Berretta, Flávio Teles, Irene L Noronha, Lúcia Andrade, Marcelo Augusto Duarte Silveira, José Manuel Condor Capcha, Talita Rojas Sanches, Roberto de Sousa Moreira, Margot S Garnica, Maria Heloisa Shimizu, Andresa Berretta, Flávio Teles, Irene L Noronha, Lúcia Andrade
Abstract
Sepsis is the leading cause of acute kidney injury (AKI) and lung injury worldwide. Despite therapeutic advances, sepsis continues to be associated with high mortality. Because Brazilian green propolis (GP) has promising anti-inflammatory, antioxidant, and immunomodulatory properties, we hypothesized that it would protect kidneys and lungs in rats induced to sepsis by cecal ligation and puncture (CLP). Male Wistar rats were divided into groups-control (sham-operated); CLP (CLP only); and CLP + GP (CLP and treatment with GP at 6 h thereafter)-all receiving volume expansion and antibiotic therapy at 6 h after the procedures. By 24 h after the procedures, treatment with GP improved survival, attenuated sepsis-induced AKI, and restored renal tubular function. Whole-blood levels of reduced glutathione were higher in the CLP + GP group. Sepsis upregulated the Toll-like receptor 4/nuclear factor-kappa B axis in lung and renal tissues, as well as increasing inflammatory cytokine levels and macrophage infiltration; all of those effects were attenuated by GP. Treatment with GP decreased the numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in renal and lung tissue, as well as protecting the morphology of the renal mitochondria. Our data open the prospect for clinical trials of the use of GP in sepsis.
Conflict of interest statement
The authors declare no competing interests.
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References
- Jawad I, Lukšić I, Rafnsson SB. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J. Glob. Health. 2012;2:010404. doi: 10.7189/jogh.01.010404.
- Bellomo R, et al. Acute kidney injury in sepsis. Intensive Care Med. 2017;43:816–828. doi: 10.1007/s00134-017-4755-7.
- Fry DE. Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues. Am. Surg. 2012;78:1–8. doi: 10.1177/000313481207800102.
- KDIGO AKI Writing Group Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for acute kidney injury. Kidney Int. 2012;2(Suppl. 2):1–141.
- Rodrigues CE, et al. Effects of continuous erythropoietin receptor activator in sepsis-induced acute kidney injury and multi-organ dysfunction. PLoS ONE. 2012;7:e29893. doi: 10.1371/journal.pone.0029893.
- Arulkumaran N, et al. Mitochondrial function in sepsis. Shock. 2016;45:271–281. doi: 10.1097/SHK.0000000000000463.
- Cóndor JM, et al. Treatment with human Wharton’s jelly-derived mesenchymal stem cells attenuates sepsis-induced kidney injury, liver injury, and endothelial dysfunction. Stem Cells Transl. Med. 2016;5:1048–1057. doi: 10.5966/sctm.2015-0138.
- Gomez H, et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock. 2014;41:3–11. doi: 10.1097/SHK.0000000000000052.
- Moreira, R.S. et al. Apolipoprotein A-I mimetic peptide 4F attenuates kidney injury, heart injury, and endothelial dysfunction in sepsis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R514–R524. Epub 2014 Jun 11 (2014).
- Erickson SE, et al. Recent trends in acute lung injury mortality: 1996–2005. Crit. Care Med. 2009;37:1574–1579. doi: 10.1097/CCM.0b013e31819fefdf.
- Endotoxin-induced lung injury in mice: Structural, functional, and biochemical responses. Am. J. Physiol. Lung Cell. Mol. Physiol.288, L333–L341 (2005).
- Liu SF, Malik AB. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. 2006;290:622–645. doi: 10.1152/ajplung.00477.2005.
- Zhou S, Wang G, Zhang W. Effect of TLR4/MyD88 signaling pathway on sepsis-associated acute respiratory distress syndrome in rats, via regulation of macrophage activation and inflammatory response. Exp. Ther. Med. 2018;15:3376–3384.
- Park DW, Zmijewski JW. Mitochondrial dysfunction and immune cell metabolism in sepsis. Infect. Chemother. 2017;49:10–21. doi: 10.3947/ic.2017.49.1.10.
- Berretta AA, et al. Propolis standardized extract (EPP-AF®), an innovative chemically and biologically reproducible pharmaceutical compound for treating wounds. Int. J. Biol. Sci. 2012;8:512–521. doi: 10.7150/ijbs.3641.
- Franchin M, et al. The use of Brazilian propolis for discovery and development of novel anti-inflammatory drugs. Eur. J. Med. Chem. 2018;153:49–55. doi: 10.1016/j.ejmech.2017.06.050.
- da Costa MF, et al. Red propolis ameliorates ischemic-reperfusion acute kidney injury. Phytomedicine. 2015;22:787–795. doi: 10.1016/j.phymed.2015.03.017.
- Nadia BH, et al. Disruption of mitochondrial membrane potential by ferulenol and restoration by propolis extract: antiapoptotic role of propolis. Acta Biol. Hung. 2009;60:385–398. doi: 10.1556/ABiol.60.2009.4.5.
- Patel S. Emerging adjuvant therapy for cancer: propolis and its constituents. J. Diet. Suppl. 2016;13:245–268. doi: 10.3109/19390211.2015.1008614.
- Szliszka E, et al. Chemical composition and anti-inflammatory effect of ethanolic extract of Brazilian green propolis on activated J774A.1 macrophages. Evid. Based Complement. Alternat. Med. 2013;2013:976415.
- Zabaiou N, et al. Biological properties of propolis extracts: Something new from an ancient product. Chem. Phys. Lipids. 2017;207(Pt B):214–222. doi: 10.1016/j.chemphyslip.2017.04.005.
- Silveira MAD, et al. Effects of Brazilian green propolis on proteinuria and renal function in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled trial. BMC Nephrol. 2019;20:140. doi: 10.1186/s12882-019-1337-7.
- de Miranda MB, et al. Hydroalcoholic extract of Brazilian green propolis modulates inflammatory process in mice submitted to a low protein diet. Biomed. Pharmacother. 2019;109:610–620. doi: 10.1016/j.biopha.2018.10.116.
- Tanaka M, et al. Protective effects of Brazilian propolis supplementation on capillary regression in the soleus muscle of hindlimb-unloaded rats. J. Physiol. Sci. 2019;69:223–233. doi: 10.1007/s12576-018-0639-z.
- Andrade L, Campos SB, Seguro AC. Hypercholesterolemia aggravates radiocontrast nephrotoxicity: protective role of L-arginine. Kidney Int. 1998;53:1736–1742. doi: 10.1046/j.1523-1755.1998.00906.x.
- Jorge LB, et al. Klotho deficiency aggravates sepsis-related multiple organ dysfunction. Am. J. Physiol. Renal Physiol. 2019;316:F438–F448. doi: 10.1152/ajprenal.00625.2017.
- Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal. Biochem. 1968;25:192–205. doi: 10.1016/0003-2697(68)90092-4.
- Capcha JMC, et al. Wharton's jelly-derived mesenchymal stem cells attenuate sepsis-induced organ injury partially via cholinergic anti-inflammatory pathway activation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2020;318:R135–R147. doi: 10.1152/ajpregu.00098.2018.
- Nusshag C, et al. Issues of acute kidney injury staging and management in sepsis and critical illness: a narrative review. Int. J. Mol. Sci. 2017;18:1387. doi: 10.3390/ijms18071387.
- Sforcin JM, Bankova V. Propolis: is there a potential for the development of new drugs? J. Ethnopharmacol. 2011;133:253–260. doi: 10.1016/j.jep.2010.10.032.
- Zhu Y, Fu Y, Lin H. Baicalin inhibits renal cell apoptosis and protects against acute kidney injury in pediatric sepsis. Med. Sci. Monit. 2016;22:5109–5115. doi: 10.12659/MSM.899061.
- Doi K, et al. Animal models of sepsis and sepsis-induced kidney injury. J. Clin. Invest. 2009;119:2868–2878. doi: 10.1172/JCI39421.
- Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat. Rev. Drug Discov. 2005;4:854–865. doi: 10.1038/nrd1854.
- Souza AC, et al. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase. Am. J. Physiol. Renal Physiol. 2012;302:F1045–F1054. doi: 10.1152/ajprenal.00148.2011.
- Leelahavanichkul A, et al. Comparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis-induced acute kidney injury and to predict mortality in CD-1 mice. Am. J. Physiol. Renal Physiol. 2014;307:F939–F948. doi: 10.1152/ajprenal.00025.2013.
- Wang W, et al. Endothelial nitric oxide synthase-deficient mice exhibit increased susceptibility to endotoxin-induced acute renal failure. Am. J. Physiol. Renal Physiol. 2004;287:F1044–F1048. doi: 10.1152/ajprenal.00136.2004.
- Schmidt C, et al. Regulation of renal sodium transporters during severe inflammation. J. Am. Soc. Nephrol. 2007;18:1072–1083. doi: 10.1681/ASN.2006050454.
- Molteni M, Gemma S, Rossetti C. The role of toll-like receptor 4 in infectious and noninfectious inflammation. Mediators Inflamm. 2016;2016:6978936. doi: 10.1155/2016/6978936.
- Chen L, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2018;9:7204–7218. doi: 10.18632/oncotarget.23208.
- Li L, et al. Caffeic acid phenethyl ester attenuates lipopolysaccharide-stimulated proinflammatory responses in human gingival fibroblasts via NF-κB and PI3K/Akt signaling pathway. Eur. J. Pharmacol. 2017;794:61–68. doi: 10.1016/j.ejphar.2016.11.003.
- Bueno-Silva B, et al. Brazilian red propolis attenuates inflammatory signaling cascade in LPS-activated macrophages. PLoS ONE. 2015;10:e0144954. doi: 10.1371/journal.pone.0144954.
- Korish AA, Arafa MM. Propolis derivatives inhibit the systemic inflammatory response and protect hepatic and neuronal cells in acute septic shock. Braz. J. Infect. Dis. 2011;15:332–338. doi: 10.1016/S1413-8670(11)70201-X.
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