Role of hypoxia during nephrogenesis

Abstract

Mammals develop in a physiologically hypoxic state, and the oxygen tension of different tissues in the embryo is precisely controlled. Deviation from normal oxygenation, such as what occurs in placental insufficiency, can disrupt fetal development. Several studies demonstrate that intrauterine hypoxia has a negative effect on kidney development. As nascent nephrons are forming from nephron progenitors in the nephrogenic zone, they are exposed to varying oxygen tension by virtue of the development of the renal vasculature. Thus, nephrogenesis may be linked to oxygen tension. However, the mechanism(s) by which this occurs remains unclear. This review focuses on what is known about molecular mechanisms active in physiological and pathological hypoxia and their effects on kidney development.

Keywords: Hypoxia; Nephrogenesis; Nephron progenitors; Placental insufficiency.

Figure 1

The hypoxia inducible factor 1 α-subunit (HIF-1α) is constitutively expressed. When the cellular oxygen tension is above 5%, HIF-1α is degraded. This is initiated when prolyl-4-hydroxylases (PHD) add hydroxyl (-OH) groups to HIF-1α. The von-Hippel Lindau protein (pVHL) binds hydroxylated HIF-1α and recruits other proteins to aid in the ubiquitinylation of HIF-1α, targeting it for degradation by the 26S proteasome. When the oxygen tension drops below 5%, PHDs can no longer hydroxylate HIF-1α, preventing pVHL from binding. HIF-1α accumulates in the cytosol and binds the HIF-1β/ARNT subunit. This heterodimeric transcription factor complex binds the CBP/p300 coactivator and this complex then translocates to the nucleus where it binds hypoxia-responsive elements (HRE) throughout the genome to up-regulate transcription of many genes involved in various processes.