There is renewed awareness of the importance of the renal epithelium generally, and the proximal tubule specifically, as both a target and a mediator in chronic kidney diseases (CKD). Numerous studies have highlighted the importance of tubulointerstitial injury as an ultimate driver of progression of kidney disease. There is also increasing evidence that effective recovery of epithelial integrity following acute kidney injury (AKI) is vital to prevent development of CKD (1). Furthermore, recent studies indicate that the proximal tubule is an important target and contributor to development of diabetic nephropathy. Our previous studies have implicated regulated activation of the EGF receptor (EGFR) in the proximal tubule as an important mediator of recovery from AKI (3) (4) and persistent aberrant EGFR activation as a significant contributor to pathologic development of tubulointerstitial fibrosis in response to hypertension and diabetes (4, 5). Although our previous studies have identified classic signaling pathways, such as the MEK/ERK1/2 and PI-3K/AKT pathways, immediately downstream of EGFR activation in mediation of these responses, the ultimate effectors of EGFR signaling that mediate the regeneration following acute injury and the aberrant responses leading to tubulointerstitial fibrosis have not been adequately elucidated. In this regard, we have recently found evidence for an important role for the HIPPO/YAP pathway in the mediation of EGFR's effects in both proximal tubule diabetic injury and in recovery from AKI (2) and preliminary data).
Aims 1 and 2 will utilize in vivo studies with both genetically modified mice and specific pharmacologic inhibitors and targeted in vitro studies to elucidate roles and mechanisms of EGFR-dependent proximal tubule YAP activation and function in both AKI (Aim 1) and CKD (Aim 2).
In Aim 3, we will employ novel models of proximal tubule- directed tubulointerstitial fibrosis to investigate the crosstalk between the tubule epithelium and renal fibroblasts. We hypothesize that aberrant proximal tubule production of lysophosphatidic acid (LPA) plays an important paracrine role to transform quiescent renal fibroblasts into active myofibroblasts. We also hypothesize that renal fibroblasts develop a dependence upon aerobic glycolysis (?Warburg phenomenon?) and that inhibition of glycolysis in these cells will prevent myofibroblast transformation and decrease development of tubulointerstitial fibrosis. There are three specific aims:
Aim I Determine the Role of EGFR Activation of the Hippo/YAP Pathway in Recovery From Acute Kidney Injury Aim 2 Determine the Role of Hippo/YAP Signaling in EGFR-Mediated Tubulointerstitial Fibrosis Aim 3 Determine the Role of EGFR in Mediating Myofibroblast Transformation and Proliferation The ultimate goal of these studies is to understand physiologic regulation of proximal tubule regeneration and the pathophysiologic mechanisms mediating the development of progressive tubulointerstitial fibrosis and to identify new targets for prevention and treatment of renal fibrosis.
Project(Narrative( ! The incidence and prevalence of both AKI and CKD are increasing in frequency and severity in the Veteran population. We have an inadequate understanding of the endogenous mechansims of epithelial repair following AKI and incomplete understanding of signaling pathways leading to progressive tubulointerstitial fibrosis. The studies in the current proposal should allow identification of the factors and/or pathways involved in both recovery from AKI and mediation of renal fibrosis that will enable us to develop in vivo strategies to ameliorate and/or ideally prevent progressive renal injury and end stage renal disease. The studies proposed in this grant will have a significant impact on the health care of our Veterans and make contribute to the research mission of the VA.
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