# Autocrine and paracrine podocyte signals decrease glomerular function/health in aged kidneys

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $778,681

## Abstract

PROJECT SUMMARY/ABSTRACT
The overall scope of the problem is that as the US population lives longer, kidney disease becomes more
abundant. In particular, elderly patients face worse disease outcomes, and they are now the largest group to
undergo first-time dialysis. The goal of this proposal is to prove that aged podocytes are central to the many
glomerular changes with aging. Changes to and loss of podocytes remain the best predictors of age-related
glomerulosclerosis and reduced GFR. Major unmet needs are understanding the mechanisms of podocyte
aging and the crosstalk between aged podocytes and neighboring parietal epithelial cells (PECs). To close
these knowledge gaps, we performed a transcriptome analysis comparing podocytes from aged vs. young
mice. Much to our surprise, transcripts for immune response processes such as inflammasome components,
inflammatory factors (e.g. TNFα, interferons, interleukins and chemokines) and SASPs were significantly
enriched. Importantly, similar changes were confirmed in human kidney biopsies.
 Based on these preliminary data, we propose a novel paradigm that aged podocytes secrete inflammatory
signals and SASPs that in autocrine loops directly impact podocytes themselves. Specific Aim #1 will prove
that this newly discovered inflammatory aged podocyte phenotype directly shortens the podocyte's lifespan
and reduces their health-span. We will test the hypotheses that in aged podocytes: (1) Inflammasome-induced
de novo intracellular inflammation reduces podocyte lifespan; (2) The PD1 signaling pathway acts downstream
of the NLRP3 inflammasome; (3) A specific subset of secreted inflammatory mediators accelerates the
podocyte aging phenotype through autocrine loops.
 We also propose a second novel paradigm in which aged podocytes play a paracrine role in accelerating
PEC aging. This is based on the facts that (i) podocyte aging temporally precedes PEC aging; (ii) PEC aging is
typically only present in individual glomeruli in which podocytes exhibit an aged phenotype; (iii) inhibition of the
inflammasome or PD1 pathways in aged podocytes reduces PEC aging. In Specific Aim #2 we propose that
SASPs and inflammatory cytokines derived from aged podocytes accelerate the PEC aging phenotype through
paracrine loops. We will test the hypotheses that: (1) The inflammatory podocyte phenotypes in aged mice
precedes and accelerates PEC aging. (2) A distinct subset of SASPs and inflammatory cytokines derived from
aged podocytes accelerates the PEC aging phenotype.
 These studies are based on many innovative experimental approaches including aging studies in transgenic
mice, primary human podocytes and PECs, Design-of-Experiment methodology and novel co-culture models.
Finally, the focus of our study is significant for its short-term translational impact by intersecting our mouse
data with a large transcriptomic data set on aged human kidneys and its long-term impact in developing
therapeutic strategies that will counter the ag...

## Key facts

- **NIH application ID:** 10520753
- **Project number:** 1R01DK128204-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Stuart James Shankland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $778,681
- **Award type:** 1
- **Project period:** 2022-09-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520753

## Citation

> US National Institutes of Health, RePORTER application 10520753, Autocrine and paracrine podocyte signals decrease glomerular function/health in aged kidneys (1R01DK128204-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10520753. Licensed CC0.

---

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