# Adaptive and maladaptive repair after kidney injury

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $636,329

## Abstract

Fibrosis is a common histological manifestation of chronic kidney disease (CKD), characterized by epithelial
atrophy, accumulation of myofibroblasts, collagen, and immune cells. The degree of fibrosis predicts kidney
function decline regardless of disease etiology. While the kidney can fully regenerate and repair following acute
kidney injury (AKI), it is believed that a maladaptive injury response plays a key role in fibrosis development.
Over the past 15 years, as part of this grant, our lab has made remarkable progress in systematically dissecting
adaptive and maladaptive regeneration, and demonstrated the role of Notch signaling in the injury and repair
process. During the first decade of this grant, we demonstrated that transient Notch activation in progenitor cells
is essential for reparative regeneration. In contrast, during fibrosis, Notch expression remains elevated in tubule
cells, hindering terminal differentiation through metabolic reprogramming.
Single cell studies have discovered an emergence of new PT cell subpopulation (named differently by various
groups), including failed repair, maladaptive, repairing, injured (iPT), and profibrotic PT (pPT) in diseased
kidneys. Experiments indicate that iPT/pPT cells secrete various chemokines, such as IL-34, which play a role
in attracting macrophages, and their role in kidney fibrosis and disease has been extensively characterized. Our
team has shown that iPT/pPT cells secrete CXCL1, attracting basophils and orchestrating fibrosis by inviting
Th17 cells. Computational analysis highlighted strong enrichment for NFKB in iPT/pPT cells. Since NFKB is
known regulator not only proinflammatory cytokines such as IL34, CXCL1, CCL2, but also key survival genes,
activation of NFKB could create a circuit that may explain the emergence of iPT/pPT and the development of
fibrosis.
Aim 1: We will systematically characterize iPT/pPT cells in mouse and rat kidney disease models, as well as in
patient samples. Specifically, we aim to identify iPT/pPT subtypes, conserved, species- and disease-specific
markers, and driver transcriptional programs. We will define the spatial iPT/pPT niche and investigate their cell-
cell interactions.
Aim 2: To understand essential molecular changes underlying the emergence of iPT/pPT, first, we will
characterize their emergence using an engineered CRISPR-Cas9 mouse line with simultaneous readout of
lineage histories and gene expression profiles at single-cell resolution. We will validate the role of mitochondrial
damage and cytokine treatment by studying isolated tubule cells.
Aim 3: We will delineate the contribution of NFKB activation to iPT/pPT differentiation, chemokine secretion,
survival, and fibrosis development by using mice with genetic deletion of pathway components.

## Key facts

- **NIH application ID:** 10812860
- **Project number:** 2R01DK076077-15
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** KATALIN SUSZTAK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $636,329
- **Award type:** 2
- **Project period:** 2007-03-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812860

## Citation

> US National Institutes of Health, RePORTER application 10812860, Adaptive and maladaptive repair after kidney injury (2R01DK076077-15). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10812860. Licensed CC0.

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