Renal epithelial cells normally exist as a fully differentiated, stable monolayer, but can be induced to dedifferentiate and proliferate (e.g. following tubular injury). This process of de-differentiation is driven by the activation of morphogenic signaling pathways that regulate cell shape change. When these pathways are activated by growth factors in a regulated, coordinated fashion, cells will undergo de-differentiation, spreading, and migration into denuded regions of the tubule, followed by proliferation and redifferentitation into a mature tubular epithelium as full confluency is achieved and pro-morphogenic responses down-regulated. Our prior work has demonstrated that transient activation of the ERK-MAPK pathway at sites of cell-matrix attachment is a key event in the initiation of these morphogenic responses, and preliminary results in both the Pkd1-/- isolated cells and in kidney sections from mouse models of PKD1 and PKD2 reveal that ERK is constitutively activated in tubular cells that are lining the cysts. Under conditions in which >95% of normal renal tubule cell lines form tubules, we have found that these Pkd1 null cells form high numbers of cysts. Our hypothesis is that the absence of Pkd1 expression leads to a failure to normally down-regulate ERK signaling as tubules mature, resulting in a sustained signal that drives cell de-differentiation, cell spreading, and cell proliferation, leading to a progressive increase in tubule diameter, i.e. a cyst. This hypothesis will be investigated by determining the site and mechanism of MAPK pathway activation in both animal models of PKD and in the cell lines derived from these mice (SA 1). The role of polycystin signaling in regulation of MAPK activation, and the consequences of sustained MAPK activation for cell morphogenesis and proliferation, will be defined (SA 2). The third specific aim will explore our additional preliminary results demonstrating that Ngal (lipocalin-2) can suppress cyst formation in Pkd1 null cells, possibly by downregulating ERK activation. In vivo models of Ngal delivery will be tested to determine the therapeutic potential of Ngal in suppressing cyst growth in PKD.
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