# Mechanisms Underlying the Susceptibility and Severity of Acute Kidney Injury

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $342,000

## Abstract

PROJECT SUMMARY
 Acute kidney injury (AKI) remains a critical health problem worldwide. AKI patients requiring renal replacement
therapy (dialysis) still have a 50-60% mortality rate. Patients survived dialysis-requiring AKI have a 28-fold
increased risk of developing progressive chronic kidney disease (CKD), leading to end stage renal disease
(ESRD). It is recognized that functioning nephrons respond to nephron deficits by increases in size and mass but
not in number. Such a growth response is called compensatory nephron hypertrophy (CNH), which can occur in
many situations in humans (e.g. surgical renal ablation due to renal trauma, tumor, congenital unilateral renal
agenesis, or donating a kidney). Although kidney donors are highly selected from healthy individuals, recent
studies have renewed our knowledge by increasingly documenting that kidney donors do have an increased risk of
developing CKD and ESRD. Our goal is to define a previously undefined pathogenic role of CNH in determining
the susceptibility and severity of AKI and in mediating accelerated development of interstitial fibrosis, a critical area
in fighting AKI and CKD. We will also investigate the molecular mechanisms by which hypertrophied nephrons are
sensitized to acute and chronic injury, with the long-term goal to identify molecular targets to reduce the incidence
of AKI and development and/or progression of CKD to ESRD. Our central hypothesis is that CNH sensitizes
nephrons to injury and initiates a cycle of nephron loss  nephron hypertrophy, consequently depleting functional
nephrons at an accelerated rate, ultimately leading to ESRD. Our expected outcomes include: 1) a revised
understanding of the traditionally so-called “compensatory renal hypertrophy” by demonstrating that hypertrophied
nephron cells are sensitized to injury; 2) identification of the vicious cycle of nephron loss  nephron hypertrophy
as a previously under-appreciated fundamental mechanism that drives progressive nephron damage; and 3)
identification of additional potential new targets for desensitizing hypertrophied nephrons from ischemic AKI. The
impact of our study will include: 1) establishment of the vicious cycle of nephron loss  nephron hypertrophy as
an important mechanism underlying the progressive nature of many kidney diseases and documenting a
deleterious aspect of CNH in sensitizing nephrons to injury; and 2) providing necessary preclinical knowledge
about the molecular mechanisms by which CNH occurs and drives progressive nephron damage. This project may
lead to development of novel and improved treatment by targeting specific signaling molecules to slow or even stop
the vicious cycle of nephron loss  nephron hypertrophy to prevent kidney disease progression. Aim 1 will define
the role of compensatory nephron hypertrophy in determining susceptibility and severity of AKI. Aim 2 will
determine the mechanisms by which compensatory nephron hypertrophy sensitizes nephrons to AKI. Aim 3 will
d...

## Key facts

- **NIH application ID:** 9966980
- **Project number:** 5R01DK114328-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** JIAN-KANG CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,000
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966980

## Citation

> US National Institutes of Health, RePORTER application 9966980, Mechanisms Underlying the Susceptibility and Severity of Acute Kidney Injury (5R01DK114328-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9966980. Licensed CC0.

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