Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Basic Science Article
  • Published:

The reduced number of nephrons with shortening renal tubules in mouse postnatal adverse environment

Pediatric Research volume 93, pages 1873–1882 (2023)Cite this article

Abstract

Background

The intrauterine adverse environment during nephrogenesis reduces the nephron number, probably associates with impaired ureteric bud (UB) branching.

Methods

The kidneys in C57/BL6 mice were irradiated with a single dose of 10 gray (10 Gy) as adverse environment on postnatal day 3 (irradiated PND3 kidneys) after UB branching ceased. The renal functions and pathological findings of irradiated PND3 kidneys were compared with those of non-irradiated control and 10 Gy irradiation on PND14 (irradiated PND14 kidney) from 1 to 18 months.

Results

The number and density of glomeruli in irradiated PND3 kidneys were reduced by 1 month with renal dysfunction at 6 months. The morphologically incomplete glomeruli with insufficient capillaries were involuted by 1 month in the superficial cortex. Reduced tubular numbers and developmental disability with shortening renal tubules occurred in irradiated PND3 kidneys with impaired urine concentration at 6 months. Hypertrophy of glomeruli developed, and occasional sclerotic glomeruli appeared in the juxtamedullary cortex with hypertension and albuminuria at 12 to 18 months.

Conclusions

The reduced number of nephrons with shortening renal tubules occurred with impaired renal functions in a postnatal adverse environment after cessation of UB branching, and glomerular hypertrophy with occasional glomerulosclerosis developed accompanied with hypertension and albuminuria in the adulthood.

Impact

  • The reduced number of nephrons with shortening renal tubules occurred with impaired renal functions in a postnatal adverse environment after cessation of ureteric bud branching.

  • The reduced number of glomeruli were associated with not only the impaired formation of glomeruli but also involution of morphologically small incomplete glomeruli after an adverse environment. The insufficiently developed nephrons were characterized by the shortening renal tubules with impaired urine concentration. In addition, glomerular hypertrophy and occasional glomerulosclerosis developed with hypertension and albuminuria in adulthood.

  • The present study can help to understand the risk of alternations of premature nephrons in preterm neonates.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Small kidneys with renal dysfunction after postnatal adverse environment.
Fig. 2: Thinning renal cortex with low number and density of glomeruli after postnatal adverse environment.
Fig. 3: Hypertrophy with enlarged capillary area in glomeruli after postnatal adverse environment.
Fig. 4: Glomerular hypertrophy and occasional global sclerotic glomeruli with renal dysfunction in adulthood after postnatal adverse environment.
Fig. 5: Decreased numbers of descending thin limbs with hypertrophy in the renal medulla and papilla after postnatal adverse environment.
Fig. 6: No significant change in the number of collecting ducts in the renal medulla and papilla after postnatal environment.

Similar content being viewed by others

References

  1. Chang, H. H. et al. Preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet 381, 223–234 (2013).

    Article  PubMed  Google Scholar 

  2. Ancel, P. Y. et al. Survival and morbidity of preterm children born at 22 through 34 weeks’ gestation in France in 2011: results of the EPIPAGE-2 cohort study. JAMA Pediatr. 169, 230–238 (2015).

    Article  PubMed  Google Scholar 

  3. Barker, D. J. & Osmond, C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1, 1077–1081 (1986).

    Article  CAS  PubMed  Google Scholar 

  4. Chantal, C., Evans, R. G., Bertram, J. F. & Moritz, K. M. Effects of dietary protein restriction on nephron number in the mouse. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1768–R1774 (2007).

    Article  Google Scholar 

  5. Walton, S. L. et al. Prolonged prenatal hypoxia selectively disrupts collecting duct patterning and postnatal function in male mouse offspring. J. Physiol. 596, 5873–5889 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Janot, M., Cortes-Dubly, M. L., Rodriguez, S. & Huynh-Do, U. Bilateral uterine vessel ligation as a model of intrauterine growth restriction in mice. Reprod. Biol. Endocrinol. 12, 62 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Goodwin, K. & Nelson, C. M. Branching morphogenesis. Development 147, dev184499 (2020).

  8. Short, K. M. et al. Global quantification of tissue dynamics in the developing mouse kidney. Dev. Cell 29, 188–202 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Hartman, H. A., Lai, H. L. & Patterson, L. T. Cession of renal morphogenesis in mice. Dev. Biol. 310, 379–387 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Harrison, M. R. et al. Management of the fetus with congenital hydronephrosis. J. Pediatr. Surg. 17, 728–742 (1982).

    Article  CAS  PubMed  Google Scholar 

  11. Chen, J. H., Tarry-Adkins, J. L., Matharu, K., Yeo, G. S. & Ozanne, S. E. Maternal protein restriction affects gene expression profiles in the kidney at weaning with implications for the regulation of renal function and lifespan. Clin. Sci. 119, 373–384 (2010).

    Article  CAS  Google Scholar 

  12. Juvet, C. et al. Renal programming by transient postnatal overfeeding: the role of senescence pathways. Front. Physiol. 11, 511 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Farahani, R. et al. Differential effects of chronic intermittent and chronic constant hypoxia on postnatal growth and development. Pediatr. Pulmonol. 43, 20–28 (2008).

    Article  PubMed  Google Scholar 

  14. Higo, S. et al. Acute graft-versus-host disease of the kidney in allogeneic rat bone marrow transplantation. PLoS ONE 26, e115399 (2014).

    Article  Google Scholar 

  15. Aratani, S. et al. Radiation-induced premature cellular senescence involved in glomerular diseases in rats. Sci. Rep. 14, 16812 (2018).

    Article  Google Scholar 

  16. Mii, A. et al. Renal thrombotic microangiopathy associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Pathol. Int. 61, 518–527 (2011).

    Article  PubMed  Google Scholar 

  17. Phifer, C. B. & Terry, L. M. Use of hypothermia for general anesthesia in preweanling rodents. Physiol. Behav. 38, 887–890 (1986).

    Article  CAS  PubMed  Google Scholar 

  18. Dijkman, H. B. et al. Glomerular involution in children with frequently relapsing minimal change nephrotic syndrome: An unrecognized form of glomerulosclerosis? Kidney Int. 71, 44–52 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Emery, J. L. & Macdonald, M. S. Involuting and scarred glomeruli in the kidneys of infants. Am. J. Pathol. 36, 713–723 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nonoguchi, H., Tomita, K. & Marumo, F. Effects of atrial natriuretic peptide and vasopressin on chloride transport in long- and short-looped medullary thick ascending limbs. J. Clin. Investig. 90, 349–357 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Leung, R. S. Radiation protection of the child from diagnostic imaging. Curr. Pediatr. Rev. 11, 235–242 (2015).

    Article  PubMed  Google Scholar 

  22. Ikezumi, Y. et al. Low birthweight and premature birth are risk factors for podocytopenia and focal segmental glomerulosclerosis. Am. J. Nephrol. 38, 149–157 (2013).

    Article  PubMed  Google Scholar 

  23. Barker, D. J. The developmental origins of chronic adult disease. Acta Paediatr. 446, 26–33 (2004).

    Google Scholar 

  24. Spitzer, A. & Brandis, M. Functional & morphologic maturation of the superficial nephrons. Relationship to total kidney function. J. Clin. Investig. 53, 279–287 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim, W. Y. et al. Descending thin limb of the intermediate loop expresses both aquaporin 1 and urea transporter A2 in the mouse kidney. Histochem. Cell Biol. 146, 1–12 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Endo, T. et al. Exploring the origin and limitation of kidney regeneration. J. Pathol. 236, 251–263 (2015).

    Article  PubMed  Google Scholar 

  27. Cosset, J. M. et al. Single dose versus fractionated total body irradiation before bone marrow transplantation: radiobiological and clinical considerations. Int. J. Radiat. Oncol. Biol. Phys. 30, 477–492 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Nielsen, S., Digiovanni, S. R., Christensen, E. I., Knepper, M. A. & Harris, H. W. Cellular and subcellular immunolocalization of vasopressin-regulated water channel in rat kidney. Proc. Natl Acad. Sci. USA 90, 11663–11667 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Thöny, H. C. et al. Histological features of glomerular immaturity in infants and small children with normal or altered tubular function. Eur. J. Pediatr. 154, S65–S68 (1995).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We express special thanks to Mr. Takashi Arai, Ms. Kyoko Wakamatsu, Ms. Arimi Ishikawa, Ms. Naomi Kuwahara, and Ms. Haruna Shimizu for expert technical assistance.

Funding

This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (KAKENHI) [grant number 20K08620 (A.S.)].

Author information

Authors and Affiliations

  1. Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan

    Masako Tagawa, Mika Terasaki, Etsuko Toda, Yusuke Kajimoto, Shinobu Kunugi, Yasuhiro Terasaki & Akira Shimizu

  2. Department of Nephrology, Nippon Medical School, Tokyo, Japan

    Akiko Mii

  3. Division of Pathology, Nippon Medical School Hospital, Tokyo, Japan

    Yasuhiro Terasaki

Authors
  1. Masako Tagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mika Terasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akiko Mii
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Etsuko Toda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yusuke Kajimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shinobu Kunugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasuhiro Terasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akira Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Masako Tagawa., A.M., Y.T., and A.S. designed the research. Mika Terasaki and A.S. directed the study. Masako Tagawa, Mika Terasaki, A.M., E.T., Y.K., S.K., Y.T., and A.S. performed the experiments and analyzed the data and pathology. Masako Tagawa, Mika Terasaki, A.M., and E.T. drafted the manuscript. S.K., Y.T., and A.S. approved the final version of the manuscript. A.S. acquired the research funding. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Akira Shimizu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All procedures performed in studies involving experimental animals were in accordance with the ethical standards of the institutional research committee at which the studies were conducted (approval number: 2009-048) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tagawa, M., Terasaki, M., Mii, A. et al. The reduced number of nephrons with shortening renal tubules in mouse postnatal adverse environment. Pediatr Res 93, 1873–1882 (2023). https://doi.org/10.1038/s41390-022-02332-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-022-02332-0

Search

Advanced search

Quick links