Molecular biological observations validate the existence of two major angiotensin II (Ang II) receptor subtypes (AT1 and AT2). While the AT1 receptor has been considered to subserve many of the biological functions linked to Ang II, emerging evidence indicates that the adult AT2 may also mediate significant biological responses as well. Several recent observations suggest that AT2 receptor mediate cell signaling to inhibition of cell growth, apoptosis, Na excretion and protein against Ang II-induced increments in BP in pathophysiological situations. Renal proximal tubular epithelial cells express a novel complement of both AT1 (basolaterally oriented) and AT2 (apically oriented) receptor subtypes that mediate Na reabsorptive, growth modulation and nutriuretic responses to Ang II. Notable differences exist between the Ang II receptor subtypes express3ed in the kidney and other locations. Of relevance to this proposal is that observation that 1) signaling linked to the kidney epithelial AT2 receptor differs from cloned fetal AT2 receptor in that the renal isoform activates a membrane associated PLA2, releases archidonic acid which is metabolized by cytochrome P450 isozymes and activates the MAP superfamily (ERK1/ERK2, JNK and P38 kinase) and 2( the renal epithelial AT2 isoform is linked to G protein betagamma.
The aims of this proposal are designed to test the hypothesis that the renal epithelial AT2 receptor has novel binding and signaling properties that involve G protein betagamma and archidonic acid as critical upstream mediators.
AIM 1 determines the molecular basis for the function of the renal AT2 Ang II receptor.
AIM 2 determines the mechanism(s) by which G-protein betagamma subunits are involved in AT2 mediated PLA2 activation and downstream events which include cytoskeletal rearrangement and mitogenesis.
AIM 3 determines the mechanism whereby non-receptor tyrosine kinases from Src superfamily and phosphoinositide 3-kinase (PI3-kinase) isoforms mediate Ang II- and arachidonic acid-induced signaling and downstream events involving cytoskeletal rearrangement and mitogenesis.. Particularly germane is the fact that arachidonic acid represents a novel mechanism whereby G protein coupled receptors (GPCRs) are linked to receptor and protein tyrosine kinases, p21/ras and the MAPK superfamily. Moreover, arachidonic acid represents a common fatty acid released on activation of a variety of signaling mediators (PLA2, PlC, PLD, etc.) and can mediate cross-talk between GPCRs and tyrosine kinase receptors.
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