Advertisement

Losartan accelerates the repair process of renal fibrosis in UUO mouse after the surgical recanalization by upregulating the expression of Tregs

  • Jie Song
  • Yangyang Xia
  • Xiang Yan
  • Jia Luo
  • Chunming Jiang
  • Miao Zhang
  • Guo-Ping Shi
  • Wei ZhuEmail author
Nephrology - Original Paper
  • 34 Downloads

Abstract

Obstructive nephropathy is a common cause for chronic kidney disease. Surgery, which is adopted to promptly relieve the obstruction, is the most important method to save damaged kidneys. However, earlier studies have shown that renal function will continue to deteriorate until the terminal stage after the obstruction’ relief. The aim of this study is to explore the renal fibrosis and investigate the effect of losartan on renal fibrosis after the obstruction’ relief using an improved mouse model of relief for unilateral ureteral obstruction (RUUO). Experiments carried out using C57BL/6 mice (n = 30) were randomly divided into RUUO + Losartan group, RUUO group and sham group. Using an improved mouse RUUO model, this study revealed that the mouse kidney for 3- or 7-day unilateral ureteral obstruction undergoing the RUUO surgery was still in a state of injury and fibrosis, while losartan could effectively ameliorate renal fibrosis by upregulating the expression of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) in kidney after the surgery of RUUO.

Keywords

RUUO Mouse model Renal fibrosis Losartan Tregs 

Notes

Acknowledgements

This work was supported by Nanjing Municipal Health and Family Planning Commission and Nanjing Health Youth Talent. We are grateful to the Nanjing Drum Tower Hospital Animal Center.

Funding

This work was supported by Nanjing Municipal Health and Family Planning Commission (ZKX17018); Nanjing Health Youth Talent (QRX17045).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 1.
    Keddis MT, Rule AD (2013) Nephrolithiasis and loss of kidney function. Curr Opin Nephrol Hypertens 22(4):390–396CrossRefGoogle Scholar
  2. 2.
    Lucarelli G, Ditonno P, Bettocchi C et al (2013) Delayed relief of ureteral obstruction is implicated in the long-term development of renal damage and arterial hypertension in patients with unilateral ureteral injury. J Urol 189(3):960–965CrossRefGoogle Scholar
  3. 3.
    Chevalier RL (2006) Pathogenesis of renal injury in obstructive uropathy. Curr Opin Pediatr 18(2):153–160CrossRefGoogle Scholar
  4. 4.
    Chevalier RL (2006) Obstructive nephropathy: towards biomarker discovery and gene therapy. Nat Clin Pract Nephrol 2(3):157–168CrossRefGoogle Scholar
  5. 5.
    Mezzano SA, Ruiz-Ortega M, Egido J (2001) Angiotensin II and renal fibrosis. Hypertension (Dallas, Tex.: 1979) 38(3 Pt 2):635–638CrossRefGoogle Scholar
  6. 6.
    Ucero AC, Benito-Martin A, Izquierdo MC et al (2014) Unilateral ureteral obstruction: beyond obstruction. Int Urol Nephrol 46(4):765–776CrossRefGoogle Scholar
  7. 7.
    Platten M, Youssef S, Hur EM et al (2009) Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc Natl Acad Sci USA 106(35):14948–14953CrossRefGoogle Scholar
  8. 8.
    Benigni A, Cassis P, Remuzzi G (2010) Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2(7):247–257CrossRefGoogle Scholar
  9. 9.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25) Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol (Baltimore, Md.: 1950) 155(3):1151–1164Google Scholar
  10. 10.
    Kinsey GR, Huang L, Vergis AL, Li L, Okusa MD (2010) Regulatory T cells contribute to the protective effect of ischemic preconditioning in the kidney. Kidney Int 77(9):771–780CrossRefGoogle Scholar
  11. 11.
    Gandolfo MT, Jang HR, Bagnasco SM et al (2009) Foxp3 + regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int 76(7):717–729CrossRefGoogle Scholar
  12. 12.
    Border WA, Noble NA (1998) Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension (Dallas, Tex.: 1979) 31(1 Pt 2):181–188CrossRefGoogle Scholar
  13. 13.
    Tapmeier TT, Brown KL, Tang Z, Sacks SH, Sheerin NS, Wong W (2008) Reimplantation of the ureter after unilateral ureteral obstruction provides a model that allows functional evaluation. Kidney Int 73(7):885–889CrossRefGoogle Scholar
  14. 14.
    Radovic N, Aralica G, Ljubanovic DG, Jelec V, Kontek M (2014) Effect of unilateral ureteral obstruction and anti-angiotensin II treatment on renal tubule cell apoptosis and interstitial fibrosis in rats. Coll Antropol 38(2):583–588Google Scholar
  15. 15.
    Radovic N, Cuzic S, Knotek M (2008) Effect of unilateral ureteral obstruction and anti-angiotensin II treatment on renal tubule and interstitial cell apoptosis in rats. Croat Med J 49(5):600–607CrossRefGoogle Scholar
  16. 16.
    Zhang Y, Kong J, Deb DK, Chang A, Li YC (2010) Vitamin D receptor attenuates renal fibrosis by suppressing the renin-angiotensin system. J Am Soc Nephrol JASN 21(6):966–973CrossRefGoogle Scholar
  17. 17.
    Jun C, Qingshu L, Ke W et al (2015) Protective effect of CXCR17(+)CD4(+)CD25(+)Foxp3(+) regulatory T cells in renal ischemia-reperfusion injury. Mediat Inflamm 2015:360973CrossRefGoogle Scholar
  18. 18.
    Mei Y, Yangyang Z, Shuai L et al (2016) Breviscapine prevents downregulation of renal water and sodium transport proteins in response to unilateral ureteral obstruction. Iran J Basic Med Sci 19(5):573–578Google Scholar
  19. 19.
    Grande MT, Lopez-Novoa JM (2009) Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol 5(6):319–328CrossRefGoogle Scholar
  20. 20.
    Klahr S, Morrissey J (2002) Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol 283(5):F861–F875CrossRefGoogle Scholar
  21. 21.
    Nishida M, Hamaoka K (2008) Macrophage phenotype and renal fibrosis in obstructive nephropathy. Nephron Exp Nephrol 110(1):e31–e36CrossRefGoogle Scholar
  22. 22.
    Bani-Hani AH, Campbell MT, Meldrum DR, Meldrum KK (2008) Cytokines in epithelial–mesenchymal transition: a new insight into obstructive nephropathy. J Urol 180(2):461–468CrossRefGoogle Scholar
  23. 23.
    Wu AK, Tran TC, Sorensen MD, Durack JC, Stoller ML (2012) Relative renal function does not improve after relieving chronic renal obstruction. BJU Int 109(10):1540–1544CrossRefGoogle Scholar
  24. 24.
    Puri TS, Shakaib MI, Chang A et al (2010) Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background. Am J Physiol Renal Physiol 298(4):F1024–F1032CrossRefGoogle Scholar
  25. 25.
    Chevalier RL, Forbes MS, Thornhill BA (2009) Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int 75(11):1145–1152CrossRefGoogle Scholar
  26. 26.
    Chaabane W, Praddaude F, Buleon M et al (2013) Renal functional decline and glomerulotubular injury are arrested but not restored by release of unilateral ureteral obstruction (UUO). Am J Physiol Renal Physiol 304(4):F432–F439CrossRefGoogle Scholar
  27. 27.
    Cao Z, Cooper ME (2001) Role of angiotensin II in tubulointerstitial injury. Semin Nephrol 21(6):554–562CrossRefGoogle Scholar
  28. 28.
    Gaedeke J, Peters H, Noble NA, Border WA (2001) Angiotensin II, TGF-beta and renal fibrosis. Contrib Nephrol 135:153–160CrossRefGoogle Scholar
  29. 29.
    De Muro P, Faedda R, Fresu P et al (2004) Urinary transforming growth factor-beta 1 in various types of nephropathy. Pharmacol Res 49(3):293–298CrossRefGoogle Scholar
  30. 30.
    Yang Y, Hou Y, Wang CL, Ji SJ (2006) Renal expression of epidermal growth factor and transforming growth factor-beta1 in children with congenital hydronephrosis. Urology 67(4):817–821 (discussion 821–812) CrossRefGoogle Scholar
  31. 31.
    Chen X, Zhu W, Al-Hayek S et al (2015) Urinary TGF-1 has a supplementary value in predicting renal function recovery post unilateral ureteral obstruction. Int Urol Nephrol 47(1):33–37CrossRefGoogle Scholar
  32. 32.
    Bottinger EP, Bitzer M (2002) TGF-beta signaling in renal disease. J Am Soc Nephrol JASN 13(10):2600–2610CrossRefGoogle Scholar
  33. 33.
    Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4+ CD25+ Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci USA 104(49):19446–19451CrossRefGoogle Scholar
  34. 34.
    Weirather J, Hofmann UD, Beyersdorf N et al (2014) Foxp3 + CD4 + T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res 115(1):55–67CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Jie Song
    • 1
  • Yangyang Xia
    • 2
  • Xiang Yan
    • 3
    • 4
  • Jia Luo
    • 2
  • Chunming Jiang
    • 2
  • Miao Zhang
    • 1
    • 2
  • Guo-Ping Shi
    • 4
  • Wei Zhu
    • 1
    • 2
    Email author
  1. 1.Department of NephrologyThe Drum Tower Clinical College of Nanjing Medical UniversityNanjingChina
  2. 2.Department of Nephrology, Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
  3. 3.Department of Urology, Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
  4. 4.Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

Personalised recommendations