# Mechanisms of Ischemic Kidney Injury and Repair

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $712,313

## Abstract

Acute kidney injury (AKI) remains a very important and growing unmet therapeutic need. The
overall goal of the studies proposed in this competitive renewal application for a grant which is
now in its 37th year of support remains to understand the mechanisms involved in kidney cell
injury and repair in order to develop therapeutic strategies for the prevention and treatment of AKI
and its chronic consequences. The current proposal builds on prior work establishing the role of
proximal tubule cells (PTCs) in adaptive and maladaptive repair. We hypothesize that kidney
PTC cell injury results in DNA damage which triggers a DNA damage response including
breast cancer 1 susceptibility protein (BRCA1), bromodomain containing protein 4 (BRD4)
activation and nuclear lamin A accumulation leading to arrest of the cell cycle, inhibition
of cell death and a senescence associated secretory phenotype (SASP). The released
chemokines and growth factors, including hedgehog proteins, then activate COUP-TFII in
the pericyte/fibroblast by a BRD4-dependent process, converting them to activated
myofibroblasts. Male and female PTC specific BRCA1 and lamin A knockout mice, wild-type
male mice and a novel transgenic “ICE” mouse with inducible DNA damage will be used in models
of ischemic, obstructive and toxic kidney injury. Animal studies including genetic modifications
with selective knockdown of BRCA1 or lamin A expression in PTCs or COUP-TFII in fibroblasts
will be complemented by inhibitor studies and human kidney organoids, tubuloids and spheroids
to enable the study of mechanisms of injury and maladaptive repair in human cell systems ex
vivo. In Specific Aim 1 we will define the roles of PTC BRCA1 and BRD4 in maladaptive repair.
We will evaluate pathways leading from DNA damage to senescence, impaired cell death, Target
of Rapamycin (TOR)-Autophagy Spatial Coupled Compartments (TASCC) generation, and
generation of pro-fibrotic growth factors and chemokines which lead to CKD. We will also evaluate
the role of BRD4, a member of the bromodomain and extraterminal (BET) family, to stabilize
BRCA1 after injury, increase senescence and inhibit death of DNA damaged cells. In Specific
Aim 2 we will define the role of PTC lamin A in the pathobiology of kidney senescence and
fibrosis. Assess the effects of lamin A and ZMPSTE24, which converts prelamin A to mature lamin
A, on PTC senescence and tissue fibrosis in response to injury in vivo, and explore cellular
mechanisms using human kidney epithelial cells, kidney organoids, and tubuloids ex vivo. In
Specific Aim 3 we will evaluate the role of COUP-TFII, BRD4 and senescence on activation of
fibroblasts, enhancement of glycolytic metabolism, and generation of profibrotic mediators.

## Key facts

- **NIH application ID:** 10812156
- **Project number:** 2R01DK039773-37A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** JOSEPH VINCENT BONVENTRE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $712,313
- **Award type:** 2
- **Project period:** 1984-09-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812156

## Citation

> US National Institutes of Health, RePORTER application 10812156, Mechanisms of Ischemic Kidney Injury and Repair (2R01DK039773-37A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10812156. Licensed CC0.

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