Prematurity in mice leads to reduction in nephron number, hypertension, and proteinuria

Abstract

The nephron number at birth is a quantitative trait that correlates inversely with the risk of hypertension and chronic kidney disease later in life. During kidney development, the nephron number is controlled by multiple factors including genetic, epigenetic, and environmental modifiers. Premature birth, which represents more than 12% of annual live births in the United States, has been linked to low nephron number and the development of hypertension later in life. In this report, we describe the development of a mouse model of prematurity-induced reduction of nephron number. Premature mice, delivered 1 and 2 days early, have 17.4 ± 2.3% (n = 6) and 23.6 ± 2% (n = 10) fewer nephrons, respectively, when compared with full-term animals (12,252 ± 571 nephrons/kidney, n = 10). After 5 weeks of age, the mice delivered 2 days premature show lower real-time glomerular filtration rate (GFR, 283 ± 13 vs 389 ± 26 μL/min). The premature mice also develop hypertension (mean arterial pressure [MAP], 134 ± 18 vs 120 ± 14 mm Hg) and albuminuria (286 ± 83 vs 176 ± 59 μg albumin/mg creatinine). This mouse model provides a proof of concept that prematurity leads to reduced nephron number and hypertension, and this model will be useful in studying the pathophysiology of prematurity-induced nephron number reductions and hypertension.

Fig 1

Nephron count and physiologic parameters in premature and full term mice. (A) The absolute nephron number per kidney in CD1 mice and in mice delivered 1-day or 2-days premature showing that the nephron number of the 2-days premature mice is less than the 1-day premature mice, and both are lower than the full-term mice. Nephron counting was performed when the mice were 30–35 days old. (B) The nephron number normalized to body weight. (C) The nephron number in full-term mice delivered by either C-section or spontaneous vaginal delivery. (D) The real-time GFR in full-term CD1 mice and in mice delivered 2 days premature. The GFR measurements were performed when the mice were 30–35 days old. (E) Urine albumin to creatinine ratio (μg albumin/mg creatinine) in full-term CD1 mice and in mice delivered 2 days premature. Urine measurements were made when the mice were 30–35 days old. (F) Mean systolic and diastolic arterial pressure measurements from conscious full-term CD1 mice and in mice delivered 2 days premature. Telemetry blood pressure measurements were obtained using implantable catheters when the mice were approximately 9 months old. The error bars represent the standard error of the mean.

Fig 2

Histology of full term and premature mouse kidneys. (A) Representative histologic images of glomeruli from full-term CD1 mice and mice delivered 2 days premature stained with periodic acid schiff reagent. (B) Bar graph comparing the measured glomerular surface in premature and full-term mice. An average of 30 glomeruli per mouse was found, and 6 mice per group were used. (C) The relative pixel density of PAS positive material in the glomeruli from full-term and premature mice. (Color version of figure is available online.)

Fig 3

A diagram depicting the hypothetical relationship between prematurity, nephron number, hypertension, and kidney disease. (Color version of figure is available online.)