Activation of Hypoxia Signaling in Stromal Progenitors Impairs Kidney Development

Abstract

Intrauterine hypoxia is a reason for impaired kidney development. The cellular and molecular pathways along which hypoxia exerts effects on nephrogenesis are not well understood. They are likely triggered by hypoxia-inducible transcription factors (HIFs), and their effects appear to be dependent on the cell compartment contributing to kidney formation. In this study, we investigated the effects of HIF activation in the developing renal stroma, which also essentially modulates nephron development fromthe metanephric mesenchyme. HIF activation was achieved by conditional deletion of the von Hippel-Lindau tumor suppressor (VHL) protein in the forkhead box FOXD1 cell lineage, from which stromal progenitors arise. The resulting kidneys showed maturation defects associated with early postnatal death. In particular, nephron formation, tubular maturation, and the differentiation of smooth muscle, renin, and mesangial cells were impaired. Erythropoietin expression was strongly enhanced. Codeletion of VHL together with HIF2A but not with HIF1A led to apparently normal kidneys, and the animals reached normal age but were anemic because of low erythropoietin levels. Stromal deletion of HIF2A or HIF1A alone did not affect kidney development. These findings emphasize the relevance of sufficient intrauterine oxygenation for normal renal stroma differentiation, suggesting that chronic activity of HIF2 in stromal progenitors impairs kidney development. Finally, these data confirm the concept that normal stroma function is essential for normal tubular differentiation.