Yuka Inage, The Jikei University School of Medicine, Tokyo, Tokyo, Japan; Kei Matsumoto, The JIKEI University, Minato-Ku, Tokyo, Japan; Daishi Hirano, The Jikei university school of medicine, Ohta-ku, Tokyo, Japan; Ryota Kobayashi, Department of Pediatrics, the Jikei University School of Medicine, Minatoku, Tokyo, Japan; Saya Yamada, The Jikei University School of Medicine, Tokyo, Tokyo, Japan; Kensuke Kumazawa, The Jikei University, Minato ku, Tokyo, Japan; Kimihiko Oishi, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
Associate Department of peidatrics, The Jikei University School of Medicine Tokyo, Tokyo, Japan
Background: Nephrogenesis is confined to the fetal period, making preterm infants inherently vulnerable to reduced nephron numbers. While various animal models have been created to replicate this condition using maternal malnutrition, glucocorticoid administration, uterine artery ligation, maternal hyperoxia, and postnatal irradiation, these approaches impact multiple organs complicating the study of isolated nephron reduction. The specific effects of nephron deficiency on renal function remains unclear in these conventional animal models. Objective: To determine whether a reduction in nephron numbers alone can lead to long-term renal dysfunction by developing a new mouse model with targeted nephron ablation. Design/Methods: We engineered mice expressing Cre recombinase under the control of the Sine oculis homeobox homolog 2 (Six2) promoter, specifically in nephron progenitor cells. These mice were crossed with loxP-diphtheria toxin receptor transgenic mice. Diphtheria toxin was administered at embryonic day 13.5 to selectively inhibit fetal nephrogenesis. Renal function was monitored up to one year, with a mice subjected to a high-salt diet (HSD). Results: The newly generated model mice had normal growth, but they exhibited significantly reduced kidney size, with approximately 50% loss of glomeruli and decreased podocyte numbers at one year of age, without other organ anomalies. Renal function of these mice began to decline as early as four weeks, as suspected by tendency toward elevated BUN levels. This decline was further exacerbated by HSD, leading to early-onset renal impairment characterized by urine albumin/creatinine ratio, blood pressure, glomerular sclerosis and low podocyte density.
Conclusion(s): We successfully generated a novel mouse model that replicates the kidney phenotype seen in preterm children with reduced number of nephrons. Our study demonstrates that a reduced number of nephrons alone predisposes to renal dysfunction, particularly under high-salt conditions. These findings suggested that preterm infants with reduced nephron numbers may be at risk for early-onset renal dysfunction and that dietary sodium restriction could be a potential preventative strategy.
