# The Intersection of Podocyte Disease and Aging

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $722,870

## Abstract

The scope of the problem is that kidney diseases become more abundant as the US population lives longer.
In particular, the risk, incidence, and prevalence of CKD increases with age. As a result, disease severity is
higher in elderly patients, the largest group to undergo first-time chronic dialysis. Injury to podocytes remains
the primary cause for glomerulosclerosis in both aging and disease. Yet, understanding the intersection of
podocyte injury and aging, and the underlying mechanisms responsible are a major unmet need. To close this
knowledge gap, our pilot studies showed that podocyte injury in young mice from two models of experimental
Focal Segmental Glomerulosclerosis (FSGS) unexpectedly induces short-term replicative- and stress-induced
premature senescence. In the long-term this results in premature podocyte aging in early middle-aged mice,
which under healthy conditions typically do not exhibit signs of senescence and aging. This phenotype was
accompanied by glomerulosclerosis and a reduced kidney function. Finally, the same correlations were also
observed in young patients with FSGS. Based on these preliminary data, we propose a novel paradigm that
podocyte injury and aging intersect, and because of these overlapping mechanisms, injury amplifies aging.
 The overall goal of this proposal is to identify novel mechanisms for podocyte injury progression with
advancing age. Specific Aim #1 will prove that injury to podocytes causes a premature aging podocyte
phenotype. This will be achieved by testing the following hypotheses: (i) Injury to non-aged podocytes causes
a p16-dependent replicative senescence and an aged phenotype; (ii) Injury to young podocytes causes a p53-
p21 axis-dependent stress-induced premature senescence; (iii) Long-term consequences of injury-induced
senescence is a premature podocyte aging phenotype causing glomerular scarring and reduced kidney
function. Specific Aim #2 will prove that the mechanisms of podocyte injury and that of aging intersect/overlap
and are amplified when superimposed on one another. We will test the following hypotheses: (i) Distinct
subpopulations of podocytes are responsible for the intersection between injury and aging; (ii) A combination of
inflammatory cytokines, immune modulators and growth factors secreted as a result of the senescent-
associated secretory phenotype triggered by podocyte injury promotes disease progression.
 Innovative experimental approaches used include two models of podocyte injury, loss-of-function
approaches using four new podocyte-specific mouse mutants to limit podocyte senescence/ aging, gain-of-
function approaches using two new podocyte-specific transgenic mice, single nuclei transcriptomics of injured
podocytes over time and the Design-of-Experiment methodology to holistically explore the podocyte signaling
environment. The proposal is significant for its short-term translational impact by integrating our mouse data
with large transcriptomic data sets from a...

## Key facts

- **NIH application ID:** 10897989
- **Project number:** 5R01AG079935-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Stuart James Shankland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $722,870
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897989

## Citation

> US National Institutes of Health, RePORTER application 10897989, The Intersection of Podocyte Disease and Aging (5R01AG079935-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10897989. Licensed CC0.

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