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Abstract: FR-PO363

Transcription Factor 21 Is Required for Normal Vascular Development of the Kidney

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Finer, Gal, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Hayashida, Tomoko, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Gomez, Roberto Ariel, University of Virginia, Charlottesville, Virginia, United States
  • Sequeira Lopez, Maria Luisa S., University of Virginia, Charlottesville, Virginia, United States
Background

Normal kidney development requires coordinated interactions between multiple progenitor cells. The Foxd1+ cells are a distinct progenitor cell population within the metanephric mesenchyme that gives rise to the stroma, the renal capsule, the mesangium, vascular smooth muscle cells (VSMCs), and pericytes. VSMCs surround larger vessels while pericytes envelop capillaries and establish direct contact with the endothelium. The specification and functional specialization of renal mural cells are poorly understood. We previously showed that the transcription factor 21 (Tcf21) in Foxd1+ cells promotes proliferation and differentiation of interstitial progenitors via enhancement of β-Catenin action on Wnt-target genes. Here, we study the role of Tcf21 in the interaction between mural cells and endothelium during nephrogenesis.

Methods

We examined Foxd1Cre;Tcf21f/f kidneys by immunostaining and in-situ hybridization.

Results

Foxd1Cre;Tcf21f/f kidneys show distorted centripetal pattern of the arterial tree with disorganized, shorter, and thinner arteries at E15.5. Additionally, Foxd1Cre;Tcf21f/f kidneys show reduced branching and aberrant ramification into the renal capsule. At E18.5, mutant kidneys have fewer vessels globally. Specifically, the mutants have smaller interlobular arteries, fewer simplified glomerular capillary loops, and disorganized peritubular capillaries in the medulla. Examination of mural cells revealed fewer layers of smooth muscle cells, fewer PDGFRβ+ CD146+ mesangial cells, and fewer CD146+ pericytes in the peritubular capillaries in mutants. These findings suggest that Tcf21 expression in Foxd1+ cells is required for normal differentiation of the mural cells hence for normal development of the kidney vasculature. Renin progenitors are a subset of the Foxd1+ cells that control renal vascular development. We next examined renin expression in Foxd1Cre;Tcf21f/f kidneys. Renin mRNA and protein were significantly reduced in mutants compared to controls. Specifically, CD146+Renin+ pericytes at the afferent arteriole of the glomerulus and around the peritubular capillaries were markedly reduced.

Conclusion

Together, our findings suggest that Tcf21 in Foxd1+ cells directs the differentiation of kidney mural cells thereby controlling the normal development of the endothelium and the overall arterial tree of the kidney.

Funding

  • NIDDK Support