Probiotics ameliorate renal ischemia-reperfusion injury by modulating the phenotype of macrophages through the IL-10/GSK-3β/PTEN signaling pathway
- 269 Downloads
After renal ischemic reperfusion injury, a series of pathological changes, such as impaired intestinal barrier function, intestinal flora, and endotoxin translocation, are caused by intestinal ischemia and hypoxia, which then trigger systemic inflammatory responses and affect the condition and prognosis of the patients. In this study, a rat model of ischemia-reperfusion injury was established by examining changes in renal function, intestinal barrier function, inflammatory index, oxidative stress, and macrophage phenotypes to evaluate the effect of probiotic VSL#3 on renal ischemia-reperfusion injury. The results showed that, after VSL#3 intervention, the levels of BUN, Scr, Cys C, PRO, and NGAL were all significantly decreased compared with the I/R group, while the value of Ccr showed a significant increase. In addition, the concentrations of MPO, IL-1β, TNF-α, IL-6, ED-1, and PCNA were all significantly lower than those in the I/R group, while the levels of endotoxin, DOA, and d-lactic acid were significantly decreased. Furthermore, the proteins associated with intestinal barrier functions, such as ZO-1, Occludin, and Claudin-1, were significantly upregulated compared with the I/R group. Overall, the VSL#3 intervention group was able to maintain the required number of beneficial intestinal flora and to inhibit the proliferation of harmful bacteria. At the same time, the VSL#3 intervention could also prevent the decrease in the levels of CAT, GSH-PX, H2O2, and T-SOD, while downregulating the expression of Keap1 and Nrf2. After the intervention with the VSL#3, the expression levels of CD68 and CD86 proteins were significantly decreased, while the expression levels of CD163 and CD206 proteins were significantly higher. Further experiments confirmed that the expression of iNOS protein was significantly decreased after the VSL#3 intervention, and the expression of Arg-1 and Ym1 proteins was significantly increased. The VSL#3 was able to induce high expressions of p-GSK-3β and p-PTEN proteins, while the use of IL-10 antibody impaired the effect of the VSL#3. In summary, this research confirms that probiotics can alleviate renal dysfunction caused by ischemia and reperfusion by protecting the intestinal barrier function and maintaining the functions of intestinal flora. The pathway screening test of this study suggests that IL-10/GSK3β/PTEN may play an important role in the process of the prototypic VSL#3 inducing M2 transformation of macrophages.
KeywordsProbiotics Renal ischemia-reperfusion injury Macrophage phenotype IL-10/GSK-3β/PTEN signaling pathway
This work was supported by the scientific and technological project of Shaanxi Province (No. 2016SF-246); the National Nature Science Foundation of China (No. 81670681); and the Major clinical research projects of the First Affiliated Hospital of Xi’an Jiao Tong University (XJTU1AF-CRF-2015-005).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 5.Carney EF (2016) Acute kidney injury: role of platelet activation and nets in renal IRI. Nat Rev Nephrol 12(12):715Google Scholar
- 6.Chen K, Xie W, Luo B, Xiao W, Teitelbaum DH, Yang H et al (2016) Intestinal mucosal barrier is injured by bmp2/4 via activation of nf-b signals after ischemic reperfusion. Mediat Inflamm 2014(3):901530Google Scholar
- 7.Dai H, Wang M, Patel PN, Kalogeris TJ, Liu Y, Durante W et al (2017) Preconditioning with the bkca channel activator ns-1619 prevents ischemia/reperfusion-induced inflammation and mucosal barrier dysfunction: ros and ho-1. Am J Physiol Heart Circ Physiol 313(5):ajpheart.00620.2016CrossRefGoogle Scholar
- 8.Ferenbach DA (2010). Role of the macrophage in acute kidney injury. University of Edinburgh, [Thesis]Google Scholar
- 9.Fan LH, Ting-Liang FU, Han XL (2017) The function and influence to intestinal barrier in ischemia-reperfusion injury. China Modern Medicine 8(11):348–351Google Scholar
- 10.Fan J, Xin J, Shao W (2017) Effects of probiotics combined with olsalazine sodium on intestinal mucosal barrier function and rage,srage in patients with ulcerative colitis. Journal of Guangxi Medical University 14(8):264–267Google Scholar
- 11.Han B, Sheng B, Zhang Z, Pu A, Yin J, Yang H (2016) Effect of aryl hydrocarbon receptor activation on intestinal mucosal barrier in mice after acute intestinal ischemia reperfusion injury. J Third Mil Med Univ 22(17):458–462Google Scholar
- 14.Li X, Pu Y, Qiu Y, Wang W, Yang H, Xiao W (2017) Effect of adenosine 2a receptor on intestinal barrier function in mice with acute reperfusion injury. J Third Mil Med Univ 27(9):382–385Google Scholar
- 15.Luo B, Chen K, Feng Q, Xiao W, Ma D, Yang H et al (2018) The interplay of bmp4 and il-7 regulates the apoptosis of intestinal intraepithelial lymphocytes under conditions of ischemia̸reperfusion. Int J Mol Med 41(5):348–352Google Scholar
- 17.Nakamura K, Zhang M, Kageyama S, Ke B, Sosa R, Reed E et al (2017) Myeloid HO-1 regulates M2 macrophage activation in liver ischemia-reperfusion injury (IRI). American Transplant Congress 17:550–550Google Scholar
- 18.Pang M, Qingping LU, Zhu L, Xia B, Zhang H (2016) Effects of probiotics to against acute diarrhea and on intestinal mucosal barrier of rats. Chin J Animal Nutr 12(6):274–277Google Scholar
- 20.Rosero O, Molnár D, Harsányi L, Szijártó A, Onody P, Kovács T et al (2014) Impaired intestinal mucosal barrier upon ischemia-reperfusion: “patching holes in the shield with a simple surgical method”. Biomed Res Int 2014(6):210901Google Scholar
- 24.Sun M, Zhang Z, Han X, Zhang X & Anesthesiology DO (2017) Breviscapine pretreatment attenuates ischemia reperfusion induced intestinal mucosal barrier damage via promoting enos/no production. J Pract MedGoogle Scholar
- 27.Tian N-q, Su Y-t, Wang X-z, General Medicine Department, Baoji Central Hospital, & Cardiology Department et al (2018) Clinical effect of probiotics combined with glutamine in the treatment of liver cirrhosis and its effect on intestinal mucosal barrier and liver function. Clinical Research and PracticeGoogle Scholar
- 29.Zhang Y, Zhang J, Nephropathy DO (2015) Mycophenolate mofetil affects toll-like receptor 4 signaling pathway of monocytes in renal ischemia/reperfusion injury(iri) of mice. Chinese Journal of Clinicians 17(13):363–366Google Scholar
- 30.Zhang Y, Zhang J, Nephropathy DO (2015) Mycophenolate mofetil affects toll-like receptor 4 signaling pathway of monocytes in renal ischemia/reperfusion injury (IRI) of mice. Chinese Journal of Clinicians (electronic version) 17(13):363–366Google Scholar