# Single-cell analysis to promote kidney repair

> **NIH NIH UC2** · WASHINGTON UNIVERSITY · 2021 · $735,509

## Abstract

Summary
Acute kidney injury (AKI) has a wide spectrum of outcomes from recovery to a long-term transition to chronic
kidney disease (CKD). Between 2000 and 2014, AKI hospitalizations have increased from 3.5 to 11.7 per 1000
persons. Medicare patients aged 66 years and older hospitalized for AKI have a 35% cumulative probability of
a recurrent AKI hospitalization within one year and 28% will be diagnosed with CKD in the same time frame.
Men have a higher risk of AKI, and of developing progressive CKD, although the mechanisms are poorly
understood. In the mouse, males also show a heightened vulnerability to AKI. Recent single cell RNA-seq
studies from the McMahon and Kim groups have highlighted marked differences in gene expression between
the sexes in proximal tubule segments, the region of the nephron most susceptible to AKI. Preliminary studies
in the Humphreys and McMahon laboratories using single nuclear sequencing identified a cell type resulting
from failed repair of proximal tubule cells (FR-PTC) following mild to severe AKI with a pro-inflammatory, pro-
fibrotic signature. FR-PTCs are hypothesized to drive progressive kidney disease following AKI. This proposal
centers on the postulates that an understanding of sex differences in response to AKI, and the application of
genetic approaches to target proinflammatory properties of FR-PTCs and to eliminate FR-PTCs following renal
repair, will be effective routes to ultimately benefit patient outcomes post AKI. To this end, we have assembled
a complementary team, with prior collaborative experience: Humphreys (Washington University), Kim
(University of Pennsylvannia) and McMahon (University of Southern California). All team members have
participated in the ReBuilding a Kidney Consortium. In Specific Aim 1: we will characterize successful versus
failed proximal tubule repair with single nucleus transcriptomics (snRNA-seq) and single nuclear chromatin
accessibility studies (scATAC-seq) in male and female mouse models examining key findings in human kidney
biopsies. In Specific Aim 2: we will harmonize multimodal datasets generated in Specific Aim1 to facilitate
viewing and interrogation of these data by the broad research community. Mining of these data by the group
will focus on defining the regulatory logic of repair strategies and outcomes in the male and female kidney. In
Specific Aim 3: we will examine the hypothesis that adverse outcomes in the male kidney following AKI are
driven by NF-kB pathway components Nfkb1 and TNIK in FR-PTCs, genetically eliminating the action of these
genes. We will generate and validate a new transgenic mouse resource for the community, enabling genetic
modification and elimination of FR-PTCs. We will determine whether FR-PTC removal has a favorable
outcome, as we predict, on progressive kidney disease following AKI.

## Key facts

- **NIH application ID:** 10247797
- **Project number:** 5UC2DK126024-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** BENJAMIN D. HUMPHREYS
- **Activity code:** UC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $735,509
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247797

## Citation

> US National Institutes of Health, RePORTER application 10247797, Single-cell analysis to promote kidney repair (5UC2DK126024-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247797. Licensed CC0.

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