# Reduced Glomerular Progenitors Impair Regeneration in Aged Kidney

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $456,533

## Abstract

The general population is living longer, precipitating the need to better understand the effects of aging on
organ structure and function. Impaired kidney function is more common in the elderly, and the incidence of
ESRD is increasing disproportionately in people > 65yrs. The goal of this grant proposal is to identify novel
mechanisms underlying changes in the aging kidney, with a focus on the glomerulus, in particular both
glomerular epithelial cell types. Kidney aging is typified by a progressive depletion of podocytes, which directly
underlies the development of glomerulosclerosis and reduced kidney function. Terminally differentiated
epithelial cells, called podocytes (podo) are unable to adequately proliferate, and therefore cannot replace
themselves. Recently a large and compelling literature shows that in young adult and middle-aged kidneys, a
subpopulation of neighboring glomerular parietal epithelial cells (PECs) serves as adult podo progenitors. We
recently reported that PECs are also affected by aging; characterized by a decrease in total PEC number, with
subpopulations of the remaining cells becoming senescent or undergoing mesenchymal transformation. This
grant proposal will study the existing problem of age-related podo depletion, but in a completely new context,
by addressing major knowledge gaps of PEC progenitors in the aging kidney and their inability to adequately
replenish podo. New approaches will include our recently developed dual PEC-podo reporter mice that
individually label and lineage trace PECs and podos within the same glomerulus, the use of an inducible PEC
progenitor reporter mouse, and the use of primary PECs in culture derived from reporter mice of advanced age.
Aim 1 will establish when, and at what rate, PEC progenitor number decreases with advancing age, and will
test the hypothesis that progressive cellular senescence is a major cause of reduced PEC progenitors with
aging. We will prove that by lowering senescence, PEC progenitor number will be higher, accompanied by
higher podocyte density. Aim 2 will prove that the self-renewal of PEC progenitors is lower in aged mice
compared to young mice, both chronically over the life span of the animal, and acutely in response to an abrupt
decline in podo number in experimental FSGS. Studies will test the hypothesis that aged PEC proliferation is
reduced due to de novo increases of the cell cycle inhibitors p21 and p16, and that this is secondary to
increased oxidative stress. Aim 3 will show that aged PEC progenitors have a lower transdifferentiation
capacity towards a podo fate, and test the hypothesis that this is in part due to the reprogramming of a subset
of aged PECs to a mesenchymal fate, thereby limiting their ability to transdifferentiate into adult podos. We
anticipate that the results will provide compelling evidence and candidate mechanisms for a new paradigm that
the biology and functional roles of PEC progenitors are markedly altered in aged kidneys thus,...

## Key facts

- **NIH application ID:** 9953937
- **Project number:** 5R01AG046231-05
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Stuart James Shankland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $456,533
- **Award type:** 5
- **Project period:** 2016-08-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953937

## Citation

> US National Institutes of Health, RePORTER application 9953937, Reduced Glomerular Progenitors Impair Regeneration in Aged Kidney (5R01AG046231-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9953937. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*