Mechanisms of Adaptive and Maladaptive Response of Renal Epithelium to Injury

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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 selective deletion of EGFR in pericytes and resident renal fibroblasts has a profound effect to limit development of tubulointerstitial injury following UUO or IR kidney injury. We propose that following ischemic injury, EGFR activation induces renal pericytes and fibroblasts to migrate and proliferate, which if left unchecked, will develop into irreversible interstitial fibrosis. We further propose that HB-EGF activation of fibroblast ErbB4 can serve as a check to limit the recruitment and proliferation of fibroblasts and their transformation into matrix-producing myofibroblasts. We propose three specific aims: Specific Aim 1 Determine the role of renal fibroblast EGFR activation in mediation of recovery from acute kidney injury and development of tubulointerstitial fibrosis Specific Aim 2 Determine the role of myeloid HB-EGF in mediation of recovery from acute injury Specific Aim 3 Determine the role of ErbB4 activation in renal fibroblasts following acute injury