Elsevier

Translational Research

Volume 159, Issue 2, February 2012, Pages 80-89
Translational Research

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

https://doi.org/10.1016/j.trsl.2011.10.004Get rights and content

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.

Section snippets

Animals, housing, and diet

The study was conducted in a 60,000 sq ft Association for Assessment and Accreditation of Laboratory Animal Care accredited animal facility devoted exclusively to housing rodents. All experimental procedures involving animals in the facility were reviewed and approved by the Medical College of Wisconsin Institutional Animal Care and Use Committee. Experimental procedures are performed in compliance with the Guide for the Care and Use of Laboratory Animals.25, 26 Accordingly, relevant ethical

Results

Data from both male and female mice were combined; we did not observe statistically significant sex difference within each group. The error bars in all data represents standard error of mean.

Histopathology

Prior studies from human and mouse models of reduced nephron number showed that the renal lesion was in the form of sclerosis of the glomeruli.35, 36 To assess whether the decrease of nephron number in our model will yield the same histopathologic picture observed in humans and other mouse models, we stained paraffin-embedded kidney sections with PAS. The glomerular surface area was measured electronically in 30 glomeruli per mouse in whole-section images captured on Hamamatsu NanoZoomer. The

Discussion

The mechanism of prematurity-induced reduction in nephron number, hypertension and chronic kidney disease (CKD) remains mostly speculative. “Organ sparing,” as a result of unfavorable intrauterine conditions, is a proposed mechanism for multiorgan underdevelopment including low nephron number,37, 38, 39, 40, 41, 42 whereas mechanical stress and hyperfiltration have been proposed as a mechanism of CKD associated with the low nephron number.35 Meanwhile, placental and environmental programming of

Ashraf El-Meanawy, MD, PhD, is an Assistant Professor of Medicine in the Division of Nephrology at the Medical College of Wisconsin. His article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, April 2011.

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    Ashraf El-Meanawy, MD, PhD, is an Assistant Professor of Medicine in the Division of Nephrology at the Medical College of Wisconsin. His article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, April 2011.

    Supported in part by grants HL-29587 and DK-62803 from the National Institutes of Health and by the Kidney Disease Center at the Medical College of Wisconsin.

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