Impact of maternal protein restriction on Hypoxia-Inducible Factor (HIF) expression in male fetal kidney development

Kidney developmental studies have demonstrated molecular pathway changes that may be related to decreased nephron numbers in the male 17 gestational days (17GD) low protein (LP) intake offspring compared to normal protein intake (NP) progeny. Here, we evaluated the HIF-1 and components of its pathway in the kidneys of 17-GD LP offspring to elucidate the molecular modulations during nephrogenesis.

Pregnant Wistar rats were allocated into two groups: NP (regular protein diet-17%) or LP (Low protein diet-6%). Taking into account miRNA transcriptome sequencing previous study (miRNA-Seq) in 17GD male offspring kidneys investigated predicted target genes and proteins related to the HIF-1 pathway by RT-qPCR and immunohistochemistry.

In the present study, in male 17-GD LP offspring, an increased elF4, HSP90, p53, p300, NFκβ, and AT2 gene encoding compared to the NP progeny. Higher labeling of HIF-1α CAP cells in 17-DG LP offspring was associated with reduced elF4 and phosphorylated elF4 immunoreactivity in LP progeny CAP cells. In 17DG LP, the NFκβ and HSP90 immunoreactivity was enhanced, particularly in the CAP area.

The current study supported that the programmed reduced nephron number in the 17-DG LP offspring may be related to changes in the HIF-1α signaling pathway. Factors that facilitate the transposition of HIF-1α to progenitor renal cell nuclei, such as increased NOS, Ep300, and HSP90 expression, may have a crucial role in this regulatory system. Also, HIF-1α changes could be associated with reduced transcription of elF-4 and its respective signaling path.