Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of alphavbeta3 integrin. Mice lacking uPAR (Plaur-/-) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active beta3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate alphavbeta3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of alphavbeta3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.

Genetic analysis in our laboratory of families with generalized thyroid hormone resistance (GTHR) has demonstrated tight linkage with a locus, c-erbAft, encoding a nuclear T3 receptor.

Glucagon (1.7 × 10−9M) stimulated gluconeogenesis, ureogenesis, lactate production, ketogenesis, proteolysis and glycogenolysis in the isolated perfused rat liver. Insulin at relatively low concentrations (10-100 μU/ml.) suppressed these metabolic effects of glucagon. When a molar glucagon:insulin ratio (2.6 or 26) was selected, which partially suppressed the stimulatory effects of glucagon and the inhibitory effects of insulin, a 100-1,000 fold change in insulin and glucagon concentration at a constant glucagon:insulin ratio, did not alter the rate of gluconeogenesis, ketogenesis, ureogenesis, glycogenolysis or lactate production. These results indicate that glucagon and insulin are complete competative antagonists in the perfused liver. This suggests that it is the glucagon:insulin ratio and not the absolute concentration of either hormone that determines their metabolic events in liver.

The platelet fibrinogen receptor, integrin ␣ IIb ␤ 3 , is a noncovalent heterodimer of glycoproteins IIb and IIIa. This work was aimed at elucidating the role played by the carboxy-terminal extracellular, transmembrane, and cytoplasmic regions of the glycoprotein ␤ 3 in the formation of functional complexes with ␣ subunits. Progressive carboxy-terminal deletions of ␤ 3 revealed that surface exposure of ␣ IIb ␤ 3 or ␣ v ␤ 3 could not occur in the absence of the transmembrane domain of ␤ 3 . In con- IntroductionThe glycoprotein (GP) IIb-IIIa complex, integrin ␣ IIb ␤ 3 , is a calcium-dependent, noncovalent heterodimer formed by GPIIb and GPIIIa. This complex is found in the plasma membrane of megakaryocytes, platelets, and some tumor tissues 1-3 and functions as a receptor for fibrinogen and other adhesive proteins like the von Willebrand factor, fibronectin, or vitronectin. 4 The ␤ 3 subunit may also complex the GP ␣ v to form the vitronectin receptor (integrin ␣ v ␤ 3 ) that shares with ␣ IIb ␤ 3 the binding of fibrinogen although with different affinity. 5 The platelet ␣ IIb ␤ 3 complex is essential to maintain a normal hemostasis. Unlike other platelet receptors that are constitutively active, the ␣ IIb ␤ 3 is maintained in a low-affinity state for its ligands. Disruption of the vascular endothelium and exposure of platelets to the action of agonists and adhesive proteins from the subendothelial matrix induces a cellular activation. The activated cells interact with adhesive proteins from the extracellular matrix, 6,7 and the ␣ IIb ␤ 3 receptors are able to bind fibrinogen with high affinity (insideout signaling), resulting in platelet aggregation. 8 Conversely, ligand-bound ␣ IIb ␤ 3 propagates signals to the interior of the cell (outside-in signaling) leading to enhanced interaction with the cytoskeleton, clustering of receptors (increased ligand avidity), and formation of focal contacts rich in signaling complexes. 9,10 The agonist-induced increase in ligand affinity of ␣ IIb ␤ 3 is thought to be the result of conformational changes of the heterodimer [11][12][13] initiated by the interaction of the cytoplasmic tails of ␣ and ␤ 3 subunits with cytosolic proteins. Despite the pathophysiologic importance of the platelet ␣ IIb ␤ 3 receptor, the knowledge of the mechanisms controlling its state of activation is rather limited.Unlike previous reports, 14 recent work from our laboratory 15 showed that a truncated form of ␤ 3 lacking the transmembrane and cytosolic domains failed to associate with ␣ IIb . The present work was aimed at further investigating the role played by the carboxyterminal domain of ␤ 3 in the surface expression and function of ␤ 3 heterodimers. The results obtained in this study indicate that surface expression of ␣ IIb ␤ 3 could not occur in the absence of the transmembrane domain of ␤ 3 . The present study has also revealed that either deletion of the carboxy-terminal region of the ␤ 3 ectodomain or disruption of the 663-687 disulfide bridge confers constitutive activity to the ␤ 3 integr...

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