Rapidly Progressive Glomerulonephritis (RPGN) is a class of acquired renal disease that remains one of few human autoimmune diseases representing an acute threat to survival. Focal necrotizing crescentic GN is the renal lesion typically associated with the clinical syndrome of RPGN and is a medical emergency that requires side-effect prone immunosuppressive therapies. Untreated RPGN progresses rapidly to renal insufficiency. During crescent formation in experimental RPGN in mice, podocytes assume a migratory phenotype and proliferate. Immune-mediated glomerulonephritis can also develop chronically. IgA nephropathy (IgAN) is the most common primary GN. The realization that around 30% of patients with this apparently benign condition progress to end-stage renal disease revealed IgAN to be a major health problem. It thus appears that a sub-group of IgAN patients undergo a phenotypic switch to accelerated disease progression and poor outcome. The basis for this switch is poorly understood, yet common pathological features between RPGN and severe IgAN may suggest that a second insult could convert IgAN to an RPGN-like phenotype, begging the question of what such an insult would be, and whether there is mechanistic convergence in the pathogenesis of the two diseases. This project relies on two recent findings in our laboratories: 1/ We demonstrated de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in podocytes from both mice and humans with RPGN. Such induction correlated with increased phosphorylation of EGFR in podocytes from mice with anti-GBM disease. Glomerular EGFR activation was absent and the course of RPGN markedly improved in HB-EGF-deficient mice. Moreover, conditional deletion of the Egfr gene from podocytes or administration of a clinically available EGFR inhibitor both markedly alleviate RPGN in mice. 2/ With the aim of identifying the pathogenic molecular pathways involved in mesangial cell transformation in IgAN, we performed a gene expression screen to identify genes induced by IgA1-complexes in human mesangial cells (HMC). HMC were stimulated by IgA1 complexes purified from IgAN patients or by serum IgA1 purified from normal subjects. HB-EGF was one of the most prominent genes up-regulated in HMC stimulated with patient-derived IgA1 complexes. These observations suggest that engagement of EGFR by HB-EGF constitutes a pathogenic switch in RPNG that may also be common to IgAN. We will first address whether the EGFR is a pathogenic mediator common to inflammatory GN. We then aim to identify pathological conversions and signaling pathways upstream of EGFR and determine to what extent they are shared in RPGN and IgAN. We are interested in defining points of mechanistic convergence between the two disease forms in attempt do identify a pathogenic switch that can convert relatively benign chronic GN such as IgAN to a rapidly progressing form of the disease. We postulate that engagement of EGFR signaling might constitute such a switch. To test this hypothesis, will first use transgenic models to address whether expression of EGFR and its ligands is sufficient to either trigger RPGN or convert IgAN to RPGN. As we anticipate that an additional insult will be required, we will then seek to identify upstream pathways and events that may elicit EGFR signaling, potentially by release of ligands such as HB-EGF. Transactivation of EGFR by G-protein-coupled receptors (GPCRs), also implicated in GN, has been documented. This interaction allows GPCRs to take advantage of pathways downstream of EGFR to influence cell function. Seeking to identify GPCRs that may engage the EGFR pathway, we focus on GPCR families likely to be engaged in both RPGN and IgAN due to dysfunction of the capillary barrier, including protease-activated receptors (PARs) and endothelin receptors (ETA and ETB). We hope to identify dominant signaling pathways of EGFR and additional targets.