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Developmental origins of disease - Effects of iron deficiency in the rat developing kidney and beyond
Anthony Babu1, Whitley N Hulse1,2, Matthew W Harer1,2
1Division of Neonatology, University of Wisconsin-Madison Department of Pediatrics, Madison, WI, USA.
Insights
Iron deficiency in pregnancy can impair fetal kidney development, leading to lasting health issues. This review highlights how early iron deficiency in rats causes kidney malformations and hypertension, suggesting risks for children.
Area of Science:
- Developmental Biology
- Pediatric Nephrology
- Nutritional Science
Background:
- Iron deficiency (ID) is a prevalent global issue during pregnancy, particularly affecting underserved populations.
- Congenital ID can lead to adverse neonatal outcomes, including impaired iron status and potential developmental effects.
- The impact of congenital ID on human kidney development remains largely unstudied, though animal models suggest risks.
Purpose of the Study:
- To review and synthesize findings from rat studies on congenital and early postnatal iron deficiency.
- To compare histological and physiological outcomes of early-life ID on kidney development.
- To contextualize these findings within molecular pathways regulating nephrogenesis.
Main Methods:
- Compilation and analysis of data from 17 published rat studies on congenital or early postnatal ID.
- Comparison of histological findings (e.g., glomerular development, fibrosis) and physiological data (e.g., renin-angiotensin signaling, hypertension).
- Integration of findings with current knowledge of nephrogenesis molecular mechanisms.
Main Results:
- Early-life ID in rats is associated with reduced kidney iron levels, fewer glomeruli, and altered glomerulogenesis.
- Observed kidney maldevelopments include larger macula densa size and interstitial fibrosis.
- Congenital ID in rats promotes renin-angiotensin system alterations and hypertension, particularly in males.
Conclusions:
- Early-life iron deficiency in rats leads to significant morphological kidney maldevelopment and altered physiological function.
- These findings support the developmental origins of health and disease (DOHaH) hypothesis regarding iron's role in kidney development.
- Urgent need for further mechanistic research in animal models to inform preventative or therapeutic strategies for children.
Abstract:
Iron is an essential cofactor in metabolic and developmental processes. Iron deficiency (ID) is the most common micronutrient deficiency in pregnancy, especially impacting medically underserved populations worldwide. Iron deficiency (ID) in pregnancy predisposes neonates to poor iron status, i.e., congenital ID and associated adverse effects. The role of congenital ID on human kidney development is unstudied, but impaired fetal kidney development is possible. Both vascular and global nutrient restriction rat models report impaired fetal kidney development, as well as induce hypertension, supporting the developmental origins of health and disease (DOHaD) hypothesis. This review compiles findings from 17 published studies in rats examining congenital or early postnatal ID, showing the same. The review compares histological and physiological findings in both congenital and postnatal ID, placing these in the context of recent knowledge describing molecular mechanistic pathways regulating nephrogenesis. Findings in rat early-life ID include lower kidney iron levels, lower glomerular generations and estimated glomerular numbers, larger maculae densa size, interstitial fibrosis, and prolonging active glomerulogenesis past normal temporal cessation. Additionally, several physiological studies in rat congenital ID promote altered renin-angiotensin signaling and hypertension with maturation, especially in males. Key findings of morphological kidney maldevelopment, altered renin-angiotensin signaling, and hypertension in early-life ID underscore the urgent need for future mechanistic data in animals such as rats. The long-term goal would be to leverage understanding from these data into either preventative or early therapeutic strategies in children.
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