# Project 2: Defining how the TGF- /FGF2 axis alters the fate of renin producing and vascular smooth muscle cells under conditions that threaten homoeostasis in infancy

> **NIH NIH P50** · UNIVERSITY OF VIRGINIA · 2024 · $216,074

## Abstract

SUMMARY/ ABSTRACT
Young children with salt wasting renal diseases are at high risk of developing chronic and severe extracellular
fluid (ECF) volume contraction, leading to growth retardation and poor renal perfusion. Chronic conditions that
threaten homeostasis such as hypotension, hypokalemia, salt depletion, and/or the prolonged used of
angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) in young children
induce the recruitment of renin-producing cells with the resulting hypertrophy of the renal arterioles. This
response however, cannot be sustained for too long without affecting renal perfusion. However, it is unclear what
are the major vascular growth factors involved in this process, and how they affect the growth of renin producing
cells. Previous studies, including our own preliminary work, suggest that Transforming Growth Factor-b (TGF-b)
and Fibroblast Growth Factor-2 (FGF-2) interacting with Angiotensin II, play a key role modulating vascular tone,
hypertrophy, and proliferation of juxtaglomerular (JG) and renal vascular smooth muscle cells (RVSMC).
However, very little is known about the role that TGF-b and FGF-2 play in the regulation of renin release and the
phenotype of renin producing cells in young infants. Here, we will test the hypothesis that under conditions
that represent a physiological threat to maintain the ECF volume and/or renal perfusion in infancy, the
Ang II-TGF-b and FGF-2 axis plays a critical role maintaining the normal fate and function of renin-
producing cells and RVSMC. In addition, we hypothesize that when the balance between the RAS, TGF-b and
FGF-2 pathways is disrupted, cells programed for the renin phenotype integrate in a disorderly manner inside
the renal arterioles, precipitating the development of vascular concentric hypertrophic lesions leading to poor
renal perfusion and kidney fibrosis. Using time and cell specific conditional deletion approaches, and single cell
transcriptomic analysis, we will test this hypothesis in three aims. In aim 1 we will test hypothesis that a functional
TGF-b receptor 1 signaling pathway in Ren1 + cells is necessary to sustain the hypertrophy of JG and RVSMC
in response to chronic changes in dietary Na+ / K+ intake or RAS inhibition during early postnatal life, and
determine how renin and the cAMP pathway interact with TGF-b and/or FGF-2 in JG and RVSMC to modulate
their endocrine and contractile phenotypes. In aim 2, we will test the hypothesis that FGF signaling contributes
to maintain the proper balance between the RAS and TGF-b in JG and RVSMCs under conditions of chronic
RAS stimulation and suppression in young mice. In aim 3 we will define the transcriptome profile and protein
changes that occur in renal arterioles and cells shed in the urine of young rats with poor renal perfusion induced
by Na+ depletion and RAS inhibition, and validate these findings in cells and tissues derived from young infants
undergoing similar conditions...

## Key facts

- **NIH application ID:** 10916461
- **Project number:** 5P50DK096373-13
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** PATRICIO E. RAY
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $216,074
- **Award type:** 5
- **Project period:** 2012-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916461

## Citation

> US National Institutes of Health, RePORTER application 10916461, Project 2: Defining how the TGF- /FGF2 axis alters the fate of renin producing and vascular smooth muscle cells under conditions that threaten homoeostasis in infancy (5P50DK096373-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916461. Licensed CC0.

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