Abstract
Background
Nephrogenesis occurs during the fetal period; because nephrogenesis does not occur after birth, preterm infants have low nephron numbers. However, whether a reduction in the number of pure nephrons alone affects renal function in conventional animal models remains unclear. Therefore, we aimed to examine whether differences in nephron number alone could lead to differences in future renal function by specifically ablating the nephrons.
Methods
Mice transgenic for Cre recombinase in the nephron progenitor cells were crossed with the locus of X-over P1-diphtheria toxin receptor transgenic mice. Diphtheria toxin was administered on embryonic day 13.5 to suppress fetal nephrogenesis. Various renal function assessments were performed until the maximum age of 1 year. Some mice received a high-salt diet (HSD).
Result
The mouse model showed a glomerular loss of approximately half per cross-sectional area and no or mild renal damage at 1 year of age. Furthermore, HSD induced the early onset and exacerbation of renal impairment.
Conclusion
The new mouse model used in this study showed HSD-induced early onset and exacerbation of renal damage, suggesting that appropriate salt management can prevent the onset and exacerbation of renal impairment in preterm infants known to have low nephron numbers.
Impact
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We established a new method for generating mice with low nephron numbers without affecting growth.
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The mouse model did not develop kidney disease but could develop mild kidney disease; however, kidney damage is exacerbated by a high-salt diet.
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Adequate salt management may prevent the future development of renal damage in infants with low nephron counts when born prematurely.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We would like to thank T. Tamatsukuri, H. Hayashi, M. Ishida, S. Nishimura, S. Kawagoe, and T. Hayakawa for technical assistance with this study. We also thank Y. Takemura of Core Research Facilities of Jikei University School of Medicine for technical assistance with electron microscopy analysis and Editage (www.editage.jp) for English language editing. This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (KAKENHI) (grant numbers 20K17258 and 23K07725) and the Kidney Research Initiative-Japan (KRI-J: Japan Kidney Association and Nippon Boehringer Ingelheim Joint Research Project).
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Y.I., Kei Matsumoto, K.H., and D.H. made substantial contributions to the study conception and design and data acquisition, analysis, and interpretation. Kenji Matsui, Y.K., Keita Morimoto, N.K., Shutaro Yamamoto, T.F., S.F., and Shuichiro Yamanaka contributed to the methodology and data collection. K.O., E.K., and T.Y. were major contributors to the review and editing of the manuscript. All the authors discussed the results and reviewed the final manuscript.
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Yuka Inage, Kei Matsumoto, Kenji Matsui, Yoshitaka Kinoshita, Keita Morimoto, Nagisa Koda, Shutaro Yamamoto, Toshinari Fujimoto, Shohei Fukunaga, Kotaro Haruhara, Shuichiro Yamanaka, Daishi Hirano, Kimihiko Oishi, and Takashi Yokoo declare that they have no conflicts of interest or financial conflicts to disclose. Eiji Kobayashi is the Chief Information Officer of Kobayashi Regeneration Research Institute, LLC. The funders had no role in the study design, collection, analyses, or interpretation of data, writing of the manuscript, or decision to publish the results.
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Inage, Y., Matsumoto, K., Haruhara, K. et al. A novel mouse model for investigating the long-term impact of reduced nephron numbers on renal function and salt sensitivity. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04123-9
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DOI: https://doi.org/10.1038/s41390-025-04123-9
