Mechanisms of Adaptive and Maladaptive Response of Renal Epithelium to Injury

急性肾损伤(AKI)在美国普通人群中的发病率正在增加，特别是在 退伍军人医疗系统服务的退伍军人人数。我们和其他人的研究表明，与生俱来的 免疫系统既是急性肾损伤早期肾损害的促进者，又是恢复过程的中介者。 此外，在恢复期，间质基质细胞被激活，并瞬时增加细胞外 矩阵生产，这可以帮助保持结构的完整性。除了发病率和死亡率的增加 由于AKI的一次发作，不完全恢复可能导致持续的肌成纤维细胞激活，从而导致 肾小管间质纤维化与慢性肾脏疾病的发展。 ErbB受体家族由EGFR(ErbB1)组成，由EGFR配体激活，包括EGF， 被激活的转化生长因子-α、血红蛋白-表皮生长因子、两调节蛋白、β细胞蛋白、表型和表型调节蛋白以及ErbB3和ErbB4 通过中性调节蛋白1-4。ERBB2不包含细胞外配体结合结构域，可作为结合 其他受体的伙伴。HB-EGF除了能激活EGFR外，还能激活ErbB4。我们已经研究过 肾上皮细胞表皮生长因子受体在急慢性肾损伤反应中的作用。我们发现选择性删除 近端肾小管上皮细胞表皮生长因子受体延迟缺血再灌注(IR)肾损伤的恢复[Chen，2012#13872]， 但持续的EGFR激活会导致肾小管间质纤维化的发展[Chen，2011#7520；Zhang， 2019年#16570}。相反，我们最近发现，抑制ErbB4会增加肾小管间质的损伤 单侧输尿管梗阻(UUO)或IR肾损伤[曾，2018年#16565}。然而，我们不确定 涉及的ErbB配体(S)。 除了上皮细胞外，我们还发现EGFR和ErbB4在髓系细胞中表达(特别是 巨噬细胞和中性粒细胞)。EGFR激活促进巨噬细胞的致炎表型，并且 我们最近的研究表明，选择性的髓系EGFR缺失促进了IR肾损伤的恢复和 抑制肾小管间质纤维化的发展。我们也在缺失基因的小鼠身上发现了类似的反应 表皮生长因子受体的配体，两性调节素。相反，我们现在发现选择性的髓系缺失HB-EGF抑制 恢复IR损伤，促进肾小管间质纤维化的发展。因此，我们建议肾脏 髓系HB-EGF直接激活上皮细胞EGFR以促进急性损伤的恢复 髓系和上皮ErbB4均可抑制随后发生的肾小管间质纤维化。 在初步研究中，我们还发现EGFR在肾脏的间质细胞、周细胞中表达。 和常驻成纤维细胞。尽管EGFR配体-EGFR轴在肾间质细胞中的作用 间质基质产生的改变以前没有被研究过，在我们的初步研究中，我们 已经发现选择性缺失EGFR对周细胞和肾脏成纤维细胞有深远的影响 限制UUO或IR肾损伤后肾小管间质损伤的发展。我们建议如下 缺血损伤，EGFR激活诱导肾周细胞和成纤维细胞迁移和增殖，如果离开 如不加以控制，将发展为不可逆转的间质纤维化。我们进一步提出，HB-EGF激活 成纤维细胞ErbB4可以作为一种检查，以限制成纤维细胞的招募和增殖及其 转化为产生基质的肌成纤维细胞。我们提出三个具体目标： 特异性目的1确定肾成纤维细胞EGFR活化在急性肾功能恢复中的作用 肾小管间质纤维化的损伤与发展 特异性目的2确定髓系HB-EGF在急性损伤恢复中的调节作用 特异性目标3确定ErbB4激活在急性损伤后肾成纤维细胞中的作用

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