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Maternal inflammation exacerbates neonatal hyperoxia-induced kidney injury in rat offspring



Preclinical studies have demonstrated that maternal inflammation or neonatal hyperoxia adversely affects kidney maturation. This study explored whether prenatal lipopolysaccharide (LPS) exposure can augment neonatal hyperoxia-induced kidney injury.


Pregnant Sprague–Dawley rats received intraperitoneal injections of LPS (0.5 mg/kg) in normal saline (NS) or NS on 20 and 21 days of gestation. The pups were reared in room air (RA) or 2 weeks of 85% O2, creating the four study groups, NS + RA, NS + O2, LPS + RA, and LPS + O2. Kidneys were taken for oxidase stress and histological analyses.


The rats exposed to maternal LPS or neonatal hyperoxia exhibited significantly higher kidney injury score, lower glomerular number, higher toll-like receptor 4 (TLR4), myeloperoxidase (MPO), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) expressions, and higher MPO activity compared with the rats exposed to maternal NS and neonatal RA. The rats exposed to both maternal LPS and neonatal hyperoxia exhibited significantly lower glomerular number, higher kidney injury score, TLR4, MPO, and 8-OHdG expressions compared with the rats exposed to maternal LPS or neonatal hyperoxia.


Maternal inflammation exacerbates neonatal hyperoxia-induced kidney injury and the underlying mechanism may be related to activation of TLR4 and increased oxidative stress.

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  1. 1.

    Hagberg, H., Wennerholm, U. B. & Savman, K. Sequelae of chorioamnionitis. Curr. Opin. Infect. Dis. 15, 301–306 (2002).

  2. 2.

    Gayle, D. A. et al. Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R1024–R1029 (2004).

  3. 3.

    Beloosesky, R., Gayle, D. A. & Ross, M. G. Maternal N-acetylcysteine suppresses fetal inflammatory cytokine responses to maternal lipopolysaccharide. Am. J. Obstet. Gynecol. 195, 1053–1057 (2006).

  4. 4.

    Wang, J. et al. Prenatal exposure to lipopolysaccharide alters renal DNA methyltransferase expression in rat offspring. PLoS ONE 12, e0169206 (2017).

  5. 5.

    Wang, X. et al. Prenatal lipopolysaccharide exposure results in dysfunction of the renal dopamine D1 receptor in offspring. Free Radic. Biol. Med. 76, 242–250 (2014).

  6. 6.

    Torbati, D. et al. Multiple-organ effect of normobaric hyperoxia in neonatal rats. J. Crit. Care 21, 85–94 (2006).

  7. 7.

    Vento, M., Sastre, J., Asensi, M. A. & Viña, J. Room-air resuscitation causes less damage to heart and kidney than 100% oxygen. Am. J. Respir. Crit. Care Med. 172, 1393–1398 (2005).

  8. 8.

    Perrone, S. et al. Oxidative kidney damage in preterm newborns during perinatal period. Clin. Biochem. 40, 656–660 (2007).

  9. 9.

    Sutherland, M. R. et al. Neonatal hyperoxia: effects on nephrogenesis and long-term glomerular structure. Am. J. Physiol. Ren. Physiol. 304, F1308–F1316 (2013).

  10. 10.

    Jiang, J. S., Chou, H. C., Yeh, T. F. & Chen, C. M. Neonatal hyperoxia exposure induces kidney fibrosis in rats. Pediatr. Neonatol. 56, 235–241 (2015).

  11. 11.

    Lahra, M. M., Beeby, P. J. & Jeffery, H. E. Maternal versus fetal inflammation and respiratory distress syndrome: a 10-year hospital cohort study. Arch. Dis. Child Fetal Neonatal Ed. 94, F13–F16 (2009).

  12. 12.

    Zoetis, T. & Hurtt, M. E. Species comparison of anatomical and functional renal development. Birth Defects Res. B 68, 111–120 (2003).

  13. 13.

    Seely, J. C. A brief review of kidney development, maturation, developmental abnormalities, and drug toxicity: juvenile animal relevancy. J. Toxicol. Pathol. 30, 125–133 (2017).

  14. 14.

    OECD. Draft OECD Guideline for Testing of Chemicals on Reproduction/Developmental Toxicity Screening Test No. 421 (Organization for Economic Co-operation and Development, Paris, 2015).

  15. 15.

    Pichler, R. H. et al. Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin. J. Am. Soc. Nephrol. 6, 1186–1196 (1995).

  16. 16.

    Raij, L., Azar, S. & Keane, W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 26, 137–143 (1984).

  17. 17.

    Sánchez, S. I., Seltzer, A. M., Fuentes, L. B., Forneris, M. L. & Ciuffo, G. M. Inhibition of angiotensin II receptors during pregnancy induces malformations in developing rat kidney. Eur. J. Pharmacol. 588, 114–123 (2008).

  18. 18.

    Ding, T. et al. Kidney protection effects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP3 inflammasome. Phytomedicine 41, 45–53 (2018).

  19. 19.

    Liu, C. et al. Mefunidone attenuates tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction. PLoS ONE 10, e0129283 (2015).

  20. 20.

    EJ, Kim et al. Involvement of oxidative stress and mitochondrial apoptosis in the pathogenesis of pelvic organ prolapse. J. Urol. 189, 588–594 (2013).

  21. 21.

    Hao, X. Q., Kong, T., Zhang, S. Y. & Zhao, Z. S. Alteration of embryonic AT(2)-R and inflammatory cytokines gene expression induced by prenatal exposure to lipopolysaccharide affects renal development. Exp. Toxicol. Pathol. 65, 433–439 (2013).

  22. 22.

    Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

  23. 23.

    Anders, H. J., Banas, B. & Schlöndorff, D. Signaling danger: toll-like receptors and their potential roles in kidney disease. J. Am. Soc. Nephrol. 15, 854–867 (2004).

  24. 24.

    El-Achkar, T. M. et al. Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am. J. Physiol. Ren. Physiol. 290, F1034–F1043 (2006).

  25. 25.

    Yiu, W. H., Lin, M. & Tang, S. C. Toll-like receptor activation: from renal inflammation to fibrosis. Kidney Int. Suppl. 4, 20–25 (2014).

  26. 26.

    Gill, R., Tsung, A. & Billiar, T. Linking oxidative stress to inflammation: Toll-like receptors. Free Radic. Biol. Med. 48, 1121–1132 (2010).

  27. 27.

    Chen, Y. et al. Attenuation of hyperoxia-induced lung injury in neonatal rats by 1α,25-dihydroxyvitamin D3. Exp. Lung Res. 41, 344–352 (2015).

  28. 28.

    Chen, C. M., Lin, W., Huang, L. T. & Chou, H. C. Human mesenchymal stem cells ameliorate experimental pulmonary hypertension induced by maternal inflammation and neonatal hyperoxia in rats. Oncotarget 8, 82366–82375 (2017).

  29. 29.

    Chou, H. C. & Chen, C. M. Neonatal hyperoxia disrupts the intestinal barrier and impairs intestinal function in rats. Exp. Mol. Pathol. 102, 415–421 (2017).

  30. 30.

    Joshi, V. D. et al. A role for Stat1 in the regulation of lipopolysaccharide-induced interleukin-1beta expression. J. Interferon Cytokine Res. 26, 739–747 (2006).

  31. 31.

    Odobasic, D., Kitching, A. R. & Holdsworth, S. R. Neutrophil-mediated regulation of innate and adaptive immunity: the role of myeloperoxidase. J. Immunol. Res. 2016, 2349817 (2016).

  32. 32.

    Toyokuni, S. et al. Quantitative immunohistochemical determination of 8-hydroxy-2′-deoxyguanosine by a monoclonal antibody N45.1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model. Lab. Invest. 76, 365e74 (1997).

  33. 33.

    Vijayaraghavan, M. et al. Dimethylarsinic acid induces 8-hydroxy-2′-deoxyguanosine formation in the kidney of NCl–Black–Reiter rats. Cancer Lett. 165, 11e7 (2001).

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Correspondence to Chung-Ming Chen.

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