Inage Yuka, Matsumoto Kei, Haruhara Kotaro, Hirano Daishi, Matsui Kenji, Kinoshita Yoshitaka, Morimoto Keita, Koda Nagisa, Yamamoto Shutaro, Fujimoto Toshinari, Fukunaga Shohei, Yamanaka Shuichiro, Oishi Kimihiko, Kobayashi Eiji, Yokoo Takashi
Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
Department of Pediatrics, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
Pediatr Res. 2025 May 27. doi: 10.1038/s41390-025-04123-9.
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.
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).
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.
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.
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.
肾发生在胎儿期进行；由于出生后不再发生肾发生，早产儿的肾单位数量较少。然而，在传统动物模型中，单纯肾单位数量减少是否会影响肾功能仍不清楚。因此，我们旨在通过特异性消融肾单位来研究单纯肾单位数量的差异是否会导致未来肾功能的差异。
将在肾祖细胞中表达Cre重组酶的转基因小鼠与X染色体失活特异性转录本-1-白喉毒素受体转基因小鼠杂交。在胚胎第13.5天给予白喉毒素以抑制胎儿肾发生。进行各种肾功能评估直至最大年龄1岁。一些小鼠接受高盐饮食（HSD）。
该小鼠模型在1岁时每个横截面积的肾小球损失约一半，且无或仅有轻度肾损伤。此外，高盐饮食导致肾功能损害提前发生并加重。
本研究中使用的新小鼠模型显示高盐饮食导致肾损伤提前发生并加重，这表明适当的盐管理可以预防已知肾单位数量低的早产儿肾功能损害发生和加重。
我们建立了一种新方法来生成肾单位数量低且不影响生长的小鼠。该小鼠模型未发生肾病，但可能发展为轻度肾病；然而，高盐饮食会加剧肾损伤。适当的盐管理可能预防早产时肾单位数量低的婴儿未来发生肾损伤。
