Skip to main content

Remote ischemic preconditioning upregulates microRNA-21 to protect the kidney in children with congenital heart disease undergoing cardiopulmonary bypass

Pediatric Nephrology volume 33, pages 911–919 (2018)Cite this article

Abstract

Background

Acute kidney injury (AKI) is one of the most common emergencies and severe diseases in the clinic. We sought to verify whether remote ischemic preconditioning (RIPC) has a protective effect on the kidney of child with congenital heart disease undergoing cardiopulmonary bypass (CPB) surgery. We hypothesized it may be related to the up-regulation of microRNA-21 (miR-21).

Methods

We performed a prospective randomized clinical study among children with congenital heart disease undergoing CPB surgery between January and December 2016. Children were randomized to an RIPC or control group. Patients in each group were divided into an AKI and a non-AKI group according to the occurrence of AKI at 48 h after surgery. Remote ischemic preconditioning (RIPC) conducted by blood-pressure cuff was performed 12 h before surgery. Serum creatinine (SCr), tumor necrosis factor-α (TNF-α), and miR-21 expression in blood and urine were measured at different time points.

Results

A total of 449 cases (200 RIPC; 249 controls) were enrolled. The male/female ratio was 1.18, with a mean age of 37.50 ± 25.31 months. The incidence of AKI in the RIPC group was significantly lower than that in the control group (19.0% vs. 46.2%, P<0.01). In further analysis, at 6 h, 24 h, and 48 h after CPB operation, blood TNF-α levels were significantly lower in the RIPC group than in the control group (P<0.01); at 24 h, 48 h, and 72 h, urine TNF-α levels were significantly lower in the RIPC group than in the control group (P<0.05). Urine and blood miR-21 expression in the RIPC group increased significantly, while there was no obvious change in the control group.

Conclusions

Remote ischemic preconditioning has a protective effect on the kidney in children with congenital heart disease, which may be related with the up-regulation of miR-21 and down-regulating the inflammatory mediator, such as TNF-α.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Ali T, Khan I, Simpson W, Prescott G, Townend J, Smith W, Macleod A (2007) Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol 18(4):1292–1298

    CAS  Article  PubMed  Google Scholar 

  2. Murugan R, Kellum JA (2011) Acute kidney injury: what’s the prognosis? Nat Rev Nephrol 7(4):209–217

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Shaw A (2012) Update on acute kidney injury after cardiac surgery. J Thorac Cardiovasc Surg 143(3):676–681

    Article  PubMed  Google Scholar 

  4. Li S, Krawczeski CD, Zappitelli M, Devarajan P, Thiessen-Philbrook H, Coca SG, Kim RW, Parikh CR (2011) Incidence, risk factors, and outcomes of acute kidney injury after pediatric cardiac surgery: a prospective multicenter study. Crit Care Med 39(6):1493–1499

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ho J, Reslerova M, Gali B, Nickerson PW, Rush DN, Sood MM, Bueti J, Komenda P, Pascoe E, Arora RC, Rigatto C (2012) Serum creatinine measurement immediately after cardiac surgery and prediction of acute kidney injury. Am J Kidney Dis 59(2):196–201

    CAS  Article  PubMed  Google Scholar 

  6. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74(5):1124–1136

    CAS  Article  PubMed  Google Scholar 

  7. Cheng Y, Zhu P, Yang J, Liu X, Dong S, Wang X, Chun B, Zhuang J, Zhang C (2010) Ischaemic preconditioning-regulated miR-21 protects heart against ischaemia/reperfusion injury via anti-apoptosis through its target PDCD4. Cardiovasc Res 87(3):431–439

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Guan J, Li H, Lv T, Chen D, Yuan Y, Qu S (2013) Bone morphogenetic protein-7 (BMP-7) mediates ischemic preconditioning-induced ischemic tolerance via attenuating apoptosis in rat brain. Biochem Biophys Res Commun 441(3):560–566

    CAS  Article  PubMed  Google Scholar 

  9. Ren Z, Cui G, Lu H, Chen X, Jiang J, Liu H, He Y, Ding S, Hu Z, Wang W, Zheng S (2013) Liver ischemic preconditioning (IPC) improves intestinal microbiota following liver transplantation in rats through 16s rDNA-based analysis of microbial structure shift. PLoS One 8(10):e75950

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Weiss JB, Eisenhardt SU, Stark GB, Bode C, Moser M, Grundmann S (2012) MicroRNAs in ischemia-reperfusion injury. Am J Cardiovasc Dis 2(3):237–247

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lorenzen JM, Batkai S, Thum T (2013) Regulation of cardiac and renal ischemia-reperfusion injury by microRNAs. Free Radic Biol Med 64:78–84

    CAS  Article  PubMed  Google Scholar 

  12. Godwin JG, Ge X, Stephan K, Jurisch A, Tullius SG, Iacomini J (2010) Identification of a microRNA signature of renal ischemia reperfusion injury. Proc Natl Acad Sci U S A 107(32):14339–14344

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Kaushal GP (2012) Autophagy protects proximal tubular cells from injury and apoptosis. Kidney Int 82(12):1250–1253

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Liu F, Lou YL, Wu J, Ruan QF, Xie A, Guo F, Cui SP, Deng ZF, Wang Y (2012) Upregulation of microRNA-210 regulates renal angiogenesis mediated by activation of VEGF signaling pathway under ischemia/perfusion injury in vivo and in vitro. Kidney Blood Press Res 35(3):182–191

    Article  PubMed  Google Scholar 

  15. Li Z, Deng X, Kang Z, Wang Y, Xia T, Ding N, Yin Y (2015) Elevation of miR-21, through targeting MKK3, may be involved in ischemia pretreatment protection from ischemia-reperfusion induced kidney injury. J Nephrol 29:27–36

    Article  PubMed  Google Scholar 

  16. The KDIGO Acute Kidney Injury Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int 2(Suppl):1–138

    Google Scholar 

  17. Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN (2006) Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 47(11):2277–2282

    Article  PubMed  Google Scholar 

  18. Mouton R, Pollock J, Soar J, Mitchell DC, Rogers CA (2015) Remote ischaemic preconditioning versus sham procedure for abdominal aortic aneurysm repair: an external feasibility randomized controlled trial. Trials 16(1):377

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jenkins KJ (2004) Risk adjustment for congenital heart surgery: the RACHS-1 method. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 7:180–184

    Article  Google Scholar 

  20. Zimmerman RF, Ezeanuna PU, Kane JC, Cleland CD, Kempananjappa TJ, Lucas FL, Kramer RS (2011) Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. Kidney Int 80(8):861–867

    Article  PubMed  Google Scholar 

  21. Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, Price V, Tsagakis K, Neuhäuser M, Peters J, Jakob H, Heusch G (2013) Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet 382(9892):597–604

    Article  PubMed  Google Scholar 

  22. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A (2007) Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11(2):R31

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xu XH, Chen Q, Chen Y, Lv LX, Zhu CQ, Dai HL, Qian JQ (2010) Effect of ethyl pyruvate on expression of inflammatory factors and mitogen-activated protein kinase proteins in renal ischemic/reperfusion injury in BABL/c mice. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 22(12):750–753

    CAS  PubMed  Google Scholar 

  24. Ma T, Liu XW, Liu Z (2013) Function of the p38MAPK-HSP27 pathway in rat lung injury induced by acute ischemic kidney injury. Biomed Res Int 2013:981235

    PubMed  PubMed Central  Google Scholar 

  25. Ma FY, Tesch GH, Flavell RA, Davis RJ, Nikolic-Paterson DJ (2007) MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney. Am J Physiol Renal Physiol 293(5):F1556–F1563

    CAS  Article  PubMed  Google Scholar 

  26. Ramachandran K, Saikumar J, Bijol V, Koyner JL, Qian J, Betensky RA, Waikar SS, Vaidya VS (2013) Human miRNome profiling identifies microRNAs differentially present in the urine after kidney injury. Clin Chem 59(12):1742–1752

    CAS  Article  PubMed  Google Scholar 

  27. Du J, Cao X, Zou L, Chen Y, Guo J, Chen Z, Hu S, Zheng Z (2013) MicroRNA-21 and risk of severe acute kidney injury and poor outcomes after adult cardiac surgery. PLoS One 8(5):e63390

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Xu X, Kriegel AJ, Liu Y, Usa K, Mladinov D, Liu H, Fang Y, Ding X, Liang M (2012) Delayed ischemic preconditioning contributes to renal protection by upregulation of miR-21. Kidney Int 82(11):1167–1175

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Luca MC, Liuni A, McLaughlin K, Gori T, Parker JD (2013) Daily ischemic preconditioning provides sustained protection from ischemia-reperfusion induced endothelial dysfunction: a human study. J Am Heart Assoc 2(1):e75

    Article  Google Scholar 

  30. Dong S, Cheng Y, Yang J, Li J, Liu X, Wang X, Wang D, Krall TJ, Delphin ES, Zhang C (2009) MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction. J Biol Chem 284(43):29514–29525

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283(2):1026–1033

    CAS  Article  PubMed  Google Scholar 

  32. Cheng Y, Zhang C (2010) MicroRNA-21 in cardiovascular disease. J Cardiovasc Transl Res 3(3):251–255

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhou X, Zhang J, Jia Q, Ren Y, Wang Y, Shi L, Liu N, Wang G, Pu P, You Y, Kang C (2010) Reduction of miR-21 induces glioma cell apoptosis via activating caspase 9 and 3. Oncol Rep 24(1):195–201

    CAS  PubMed  Google Scholar 

  34. Zhou X, Ren Y, Moore L, Mei M, You Y, Xu P, Wang B, Wang G, Jia Z, Pu P, Zhang W, Kang C (2010) Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Investig 90(2):144–155

    CAS  Article  PubMed  Google Scholar 

  35. Papagiannakopoulos T, Shapiro A, Kosik KS (2008) MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res 68(19):8164–8172

    CAS  Article  PubMed  Google Scholar 

  36. Zhang G, He LS, Wong YH, Qian PY (2013) MKK3 was involved in larval settlement of the barnacle Amphibalanus amphitrite through activating the kinase activity of p38MAPK. PLoS One 8(7):e69510

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81(2):807–869

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by grants from the Natural Science Fund of Hunan Province (2015JJ4029) and Clinical Center for Acute Renal Injury in Children of Hunan Province.

Author information

Affiliations

  1. Department of Nephrology and Rheumatology of Hunan Children’s Hospital, 86 Ziyuan Road, Changsha, Hunan, 410007, People’s Republic of China

    Zhijuan Kang, Zhihui Li, Ying Wang, Tuanhong Xia & Yuhang Zhou

  2. Academy of Pediatrics of University of South China, 86 Ziyuan Road, Changsha, Hunan, 410007, People’s Republic of China

    Zhijuan Kang, Zhihui Li, Ying Wang, Tuanhong Xia & Yuhang Zhou

  3. Department of Cardiothoracic Surgery of Hunan Children’s Hospital, 86 Ziyuan Road, Changsha, Hunan, 410007, People’s Republic of China

    Peng Huang, Jinwen Luo & Pingbo Liu

Authors
  1. Zhijuan Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhihui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinwen Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pingbo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tuanhong Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuhang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhihui Li.

Ethics declarations

Ethical considerations

The study complies with the Helsinki declaration and was approved by the local institutional ethics committee of the Hunan Children’s Hospital (ICF2015004), dated 25 November 2015. Informed consent from potential trial participants was obtained from a parent or guardian before enrollment. The model consent form Version 01 dated 5 September 2015 is available under Additional file. Patients could discontinue participation at any time upon request. The study is registered with the Chinese Clinical Trial Registry (registration ID: ChiCTR-IOC-15007513).

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kang, Z., Li, Z., Huang, P. et al. Remote ischemic preconditioning upregulates microRNA-21 to protect the kidney in children with congenital heart disease undergoing cardiopulmonary bypass. Pediatr Nephrol 33, 911–919 (2018). https://doi.org/10.1007/s00467-017-3851-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-017-3851-9

Keywords

  • Congenital heart disease
  • Cardiopulmonary bypass
  • Acute kidney injury
  • Tumor necrosis factor-α
  • MicroRNA-21
  • Children