Impact of Maternal Protein Restriction on Hypoxia-Inducible Factor (HIF) Expression in Male Fetal Kidney Development

Abstract

Background: The kidney ontogenesis is the most structurally affected by gestational protein restriction, reducing close to 30% of their functional units. The reduced nephron number is predictive of hypertension and cardiovascular dysfunctions generally observed in the adult age of most fetal programming models. We demonstrate HIF-1 predicts molecular pathway changes may be associated with the decreased nephron numbers in the 17 gestational days (17GD) low protein (LP) intake male fetal kidney compared to regular protein (NP) progeny intake. Here, we evaluated the predicted targets and related pathways in the fetal kidneys of 17-GD LP offspring to elucidate the molecular modulations during nephrogenesis. Methods: Pregnant Wistar rats were allocated into two groups: NP (regular protein diet - 17%) or LP (diet-6%). Taking into account miRNA transcriptome sequencing previous study (miRNA-Seq) in 17-GD male offspring kidneys using previously described methods, was investigated predicted target genes and proteins, in particular, related to HIF-1 pathway by RT-qPCR and immunohistochemistry. Results and conclusions: The current study data supported that nephron onset impairment in the 17-DG fetus’s kidney, programmed by gestational low-protein intake, is, at least in part, related to alterations in the HIF-1α signaling pathway. Factors that facilitate the transposition of HIF-1α to the mesenchymal cell's nucleus, such as NOS, Ep300, and HSP90, may have an essential role in this regulatory process. This alteration leads to the inhibition of adaptive responses to the adverse environment, secondary to an increase in ungraded HIF-1α, possibly associated with a reduction in the transcription factor elF-4 and proteins of their respective signaling pathways. Consequently, we may suggest an early maturation process of renal cells, inhibition of nephron progenitor cell division, and reduction of renal functional units in the offspring of rats submitted to severe gestational protein restriction.