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

Award Number: R01DK124393
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Renal vascular remodeling and arteriogenesis: cues from smooth muscle progenitor cells - 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 will test the role of hypoxia on NPCs directly. 3) We will examine whether Klf4 is required for stromal differentiation and renal arteriogenesis, and whether it signals downstream of Ntn1.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $352,472 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/10/2023	NON-COMPETING CONTINUATION	$352,472
														Subtotal = $352,472

Issue Date FY: 2022 ( Subtotal = $352,472 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/13/2021	NON-COMPETING CONTINUATION	$317,224
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/12/2022	NON-COMPETING CONTINUATION	$35,248
														Subtotal = $352,472

Issue Date FY: 2021 ( Subtotal = $352,472 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/2/2021	NON-COMPETING CONTINUATION	$35,248
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/17/2020	NON-COMPETING CONTINUATION	$317,224
														Subtotal = $352,472

Issue Date FY: 2020 ( Subtotal = $341,560 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/28/2020	NEW	$341,560
														Subtotal = $341,560

Grand Total All Awards = $1,398,976

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

Award Number: R01DK124393

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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