# Renal vascular remodeling and arteriogenesis: cues from smooth muscle progenitor cells

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $352,472

## Abstract

SUMMARY
 Approximately 500,000 Americans have end-stage renal disease. Although organ function can be
supplemented using dialysis, the 10-year survival rate is just over 10%. Ex vivo organogenesis has the potential
to meet this demand by providing functional tissue for renal replacement therapy. However to effectively generate
functional kidneys in the laboratory, all cell types within the kidney and their functional ontogeny and coupling
must be understood. Renal blood vessels are one such component that is critical to the health and homeostasis
of the kidney. Building the kidney's intricate arterial network requires synchronized actions of endothelial cells
(ECs) and vascular smooth muscle cells (vSMCs) in a sequence that is poorly understood. vSMCs arise in the
developing kidney from Foxd1+ nephrogenic stromal cells (NSCs). Ablation of Foxd1 or Foxd1+ cells cause
similar defects in renal arteries suggesting Foxd1+ NSC encoded signals may govern renal arteriogenesis.
We have found that the secreted laminin-like protein Netrin-1 (Ntn1) is expressed by Foxc1+ NSCs in the
embryonic kidney. To date, the role of Ntn1 during kidney development has not been reported.
 Genetic ablation of Ntn1 from Foxd1+ NSCs (hereafter denoted as Ntn1NSCKO) blocks formation of a perfused
renal arterial tree during development. In addition, we find Ntn1NSCKO display an aberrant vSMCs-associated
cortical vasculature and increased kidney hypoxia. As development proceeds, Ntn1NSCKO also exhibit reduced
ureteric bud (UB) branching, and postnatal Ntn1NSCKO mice display delayed nephrogenesis with ~30% fewer
glomeruli. Our preliminary data identifies a critical role for Ntn1 in kidney development, but the mechanism(s) of
this regulation is unknown. In this proposal, we address this and ask which receptor is needed for kidney
formation: stromal-neogenin1, NPC-Unc5b or endothelial-Unc5b?
 We hypothesize that NSC-derived Ntn1 cell-autonomously directs vSMC lineage specification via its
receptor neogenin1 (Neo1) and the transcription factor Klf4, to instruct renal arterial tree assembly, upon
which nephron development indirectly depends. We will test this hypothesis by carrying out following aims:
1) We will test the cell autonomy of NSC-derived Ntn1 signaling during renal arterial assembly, by asking how
the stroma responds upon absence of Ntn1, where ectopic SMCs come from in the mutants, and which Ntn1
receptors (hence which cell types) are required for arterial development (which recapitulate the Ntn1 phenotype
when ablated). 2) We will examine if aberrant nephrogenesis is caused directly via Ntn1 loss in NPCs, or
indirectly due to failure of renal arteriogenesis. We will characterize failed nephrogenesis in the Ntn1 mutant
kidneys; we will use in vitro systems to see what cell types respond to Ntn1 (NPCs versus ECs); we will test
whether late deletion of Ntn1 recapitulates the Ntn1 mutant phenotype, as it bypasses failed arteriogenesis and
associated hypoxia; and lastly we ...

## Key facts

- **NIH application ID:** 10116371
- **Project number:** 5R01DK124393-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ondine B Cleaver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,472
- **Award type:** 5
- **Project period:** 2020-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116371

## Citation

> US National Institutes of Health, RePORTER application 10116371, Renal vascular remodeling and arteriogenesis: cues from smooth muscle progenitor cells (5R01DK124393-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10116371. Licensed CC0.

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