Perinatal iron deficiency causes sex-dependent alterations in renal retinoic acid signaling and nephrogenesis

Long-term alterations in kidney structure and function have been observed in offspring exposed to perinatal stressors such as iron deficiency (ID), albeit the mechanisms underlying these changes remain unclear. Here, we assessed how perinatal ID alters renal vitamin A metabolism, an important contributor to nephrogenesis, in the developing kidney. Pregnant Sprague Dawley rats were fed either an iron-restricted or-replete diet throughout gestation, and offspring were studied on postnatal day (PD)1 and 28. Maternal iron restriction results in reduced renal retinoid concentrations in male and female offspring on PD1 ( P = .005). Nephron endowment was reduced by 21% in male perinatal ID offspring ( P < .001), whereas it was unaffected in perinatal ID females. Perinatal ID resulted in sex-dependent changes in kidney retinoid synthesis and metabolism, whereby male offspring exhibited increased expression of Raldh2 and Rar/Rxr isoforms, while females exhibited unchanged or decreased expression (all interaction P < .05). Male perinatal ID offspring exhibit sex -specific enhancements of retinoic acid pathway signaling components on PD1, including Gdnf ( P < .01) and Ctnnb1 ( P < .01), albeit robust upregulation of RA transcriptional target Stra6 was observed in both sexes ( P = .006). On PD28, perinatal ID resulted in elevated renal retinoid concentrations ( P = .02) coinciding with enhanced expression of Raldh2 ( P = .04), but not any Rar isoform or Rxr. Further, perinatal ID resulted in robust upregulation of Gdnf, Ret, Ctnnb1, associated with further increases in both Cxcr4 and Stra6 (all P < .01) at PD28. Together, these data suggest perinatal ID results in sustained sex-dependent perturbations in vitamin A metabolism, which likely underlie sex-specific reductions in nephron endowment. (c) 2022 Elsevier Inc. All rights reserved.

Automated summary

Perinatal iron deficiency alters renal vitamin A metabolism in a sex-dependent manner, resulting in reduced nephron endowment in male offspring. Male offspring exhibit enhanced retinoic acid pathway signaling components, while females show unchanged or decreased expression. These findings highlight the importance of vitamin A in kidney development and the potential long-term effects of perinatal iron deficiency.