# Mechanisms of Adaptive and Maladaptive Response of Renal Epithelium to Injury

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

The incidence of acute kidney injury (AKI) is increasing in the general U.S. population and especially in the
population of veterans served by the VA medical system. Studies by us and others have implicated the innate
immune system as both a promoter of the initial kidney damage from AKI and a mediator of the recovery process.
In addition, during the recovery period, interstitial stromal cells are activated and transiently increase extracellular
matrix production, which can help maintain structural integrity. In addition to the increased morbidity and mortality
resulting from an episode of AKI, incomplete recovery can result in persistent myofibroblast activation, leading to
tubulointerstitial fibrosis and development of chronic kidney disease.
 The ErbB family of receptors consists of EGFR (ErbB1), which is activated by EGFR ligands, including EGF,
TGF-a, HB-EGF, amphiregulin, betacellulin, epigen and epiregulin, and ErbB3 and ErbB4, which are activated
by neuregulins 1-4. ErbB2 does not contain an extracellular ligand-binding domain and serves as a binding
partner for the other receptors. In addition to activating EGFR, HB-EGF can also activate ErbB4. We have studied
the role of renal epithelial EGFR in response to acute and chronic kidney injury. We found that selective deletion
of proximal tubule EGFR delayed recovery from ischemia-reperfusion (IR) kidney injury {Chen, 2012 #13872},
but persistent EGFR activation resulted in development of tubulointerstitial fibrosis {Chen, 2011 #7520;Zhang,
2019 #16570}. In contrast, we recently found that inhibition of ErbB4 increased tubulointerstitial injury in response
to either unilateral ureteral obstruction (UUO) or IR renal injury {Zeng, 2018 #16565}. However, we not identify
the ErbB ligand(s) involved.
 In addition to epithelial cells, we find that EGFR and ErbB4 are expressed in myeloid cells (specifically
macrophages and neutrophils). EGFR activation promotes a proinflammatory phenotype in macrophages, and
our recent studies indicate that selective myeloid deletion of EGFR promotes recovery from IR kidney injury and
inhibits development of tubulointerstitial fibrosis. We have also found similar responses in mice with deletion of
the EGFR ligand, amphiregulin. In contrast, we now find that selective myeloid deletion of HB-EGF inhibits
recovery from IR injury and promotes development of tubulointerstitial fibrosis. Therefore, we propose that renal
myeloid HB-EGF directly activates epithelial EGFR to promote recovery from acute injury and also activates
both myeloid and epithelial ErbB4 to inhibit subsequent development of tubulointerstitial fibrosis.
 In preliminary studies, we have also found that EGFR is expressed in stromal cells in the kidney, pericytes
and resident fibroblasts. Although the role of the EGFR ligand-EGFR axis in renal stromal cells to mediate
alterations in interstitial matrix production has not been previously investigated, in our preliminary studies we
have found that selectiv...

## Key facts

- **NIH application ID:** 10721352
- **Project number:** 5I01BX000320-14
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** RAYMOND C. HARRIS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721352

## Citation

> US National Institutes of Health, RePORTER application 10721352, Mechanisms of Adaptive and Maladaptive Response of Renal Epithelium to Injury (5I01BX000320-14). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10721352. Licensed CC0.

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