A novel mouse model for investigating the long-term impact of reduced nephron numbers on renal function and salt sensitivity

Yuka Inage; Kei Matsumoto; Kotaro Haruhara; Daishi Hirano; Kenji Matsui; Yoshitaka Kinoshita; Keita Morimoto; Nagisa Koda; Shutaro Yamamoto; Toshinari Fujimoto; Shohei Fukunaga; Shuichiro Yamanaka; Kimihiko Oishi; Eiji Kobayashi; Takashi Yokoo

doi:10.1038/s41390-025-04123-9

A novel mouse model for investigating the long-term impact of reduced nephron numbers on renal function and salt sensitivity

Pediatr Res. 2025 May 27. doi: 10.1038/s41390-025-04123-9. Online ahead of print.

Authors

Yuka Inage^{1

2}, Kei Matsumoto³, Kotaro Haruhara¹, Daishi Hirano², Kenji Matsui¹, Yoshitaka Kinoshita^{1

4}, Keita Morimoto¹, Nagisa Koda¹, Shutaro Yamamoto^{1

5}, Toshinari Fujimoto¹, Shohei Fukunaga¹, Shuichiro Yamanaka¹, Kimihiko Oishi², Eiji Kobayashi⁶, Takashi Yokoo¹

Affiliations

¹ Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
² Department of Pediatrics, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
³ Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan. kmatsumoto@jikei.ac.jp.
⁴ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8654, Japan.
⁵ Department of Urology, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
⁶ Department of Kidney Regenerative Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.

PMID: 40425850
DOI: 10.1038/s41390-025-04123-9

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: We established a new method for generating mice with low nephron numbers without affecting growth. The mouse model did not develop kidney disease but could develop mild kidney disease; however, kidney damage is exacerbated by a high-salt diet. Adequate salt management may prevent the future development of renal damage in infants with low nephron counts when born prematurely.