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The kidney is a major site of alpha(2)-antiplasmin production.

ABSTRACT: The serpin alpha2-antiplasmin (alpha2-AP) is the major circulating inhibitor of plasmin; it plays a determining role in the regulation of intravascular fibrinolysis, In addition to blood plasma, plasmin formation occurs in various organs where it is thought to fulfill a spectrum of functions not restricted to clot lysis. Alpha2-AP is synthesized by hepatocytes, but other possible sites of production have not been investigated. To explore the potential extravascular contribution of alpha2-AP in the regulation of proteolysis, we have isolated the murine alpha2-AP cDNA and determined its mRNA distribution in adult tissues. In addition to liver, kidneys are major sites of alpha2-AP mRNA accumulation in the mouse. The transcript is present in epithelial cells lining the convoluted portion of proximal tubules, and its accumulation is under androgen control. Human kidneys also contain high levels of alpha2-AP mRNA. Moderate amounts Of alpha2-AP mRNA are detected in other murine tissues such as muscle, intestine, central nervous system, and placenta. Our observations indicate that alpha2-AP can be synthesized in a number of tissues, where it could function as a distal regulator of plasmin-mediated extracellular proteolysis.

SUBMITTER: Menoud PA

PROVIDER: S-EPMC507332 | biostudies-other | 1996 Jun

REPOSITORIES: biostudies-other

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The kidney is a major site of alpha(2)-antiplasmin production.

Menoud P A PA Sappino N N Boudal-Khoshbeen M M Vassalli J D JD Sappino A P AP

The Journal of clinical investigation 19960601 11

The serpin alpha2-antiplasmin (alpha2-AP) is the major circulating inhibitor of plasmin; it plays a determining role in the regulation of intravascular fibrinolysis, In addition to blood plasma, plasmin formation occurs in various organs where it is thought to fulfill a spectrum of functions not restricted to clot lysis. Alpha2-AP is synthesized by hepatocytes, but other possible sites of production have not been investigated. To explore the potential extravascular contribution of alpha2-AP in t ...[more]

PMID: 8647939

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Project description:Plasmin inhibition by alpha 2-antiplasmin (alpha 2AP) is regulated by the vascular components fibrin(ogen) fragments, plasminogen and lipoprotein (a). Kinetic analysis demonstrates that CNBr-derived fibrinogen fragments completely protect plasmin from alpha 2AP. Plasminogen and 6-aminohexanoic acid decrease the rate of inhibition by 5- and 10-fold respectively. These studies show that CNBr-derived fibrinogen fragments and 6-aminohexanoic acid bind plasmin kringle(s) with binding constants of 2 micrograms/ml and 120 microM respectively, and that plasminogen binds to alpha 2AP with an affinity of 0.5 nM. The unmodulated inhibition is not effected by the presence of lipoprotein (a), but in the presence of protective CNBr-derived fibrinogen fragments the rate of inhibition is increased by the presence of the lipoprotein. The kinetics demonstrate that lipoprotein (a) binds to CNBr-derived fibrinogen fragments with an affinity of 4 nM, displacing plasmin from the protective surface. In addition, tissue-type plasminogen activator and trypsin inhibition by alpha 2AP is not slowed by the presence of CNBr-derived fibrinogen fragments or plasminogen (Pg), respectively. These kinetics suggest that the initial reversible interaction between plasmin and alpha 2AP is mediated by binding of the inhibitor to the kringle 1 domain of plasmin, with a reversible inhibition constant (Ki) of 5.0 x 10(-10) M. Under conditions where this kringle-inhibitor interaction is blocked, the reversible inhibition still occurs between the plasmin and alpha 2AP, but the initial Ki is increased to 5.0 x 10(-9) M. These data suggest that, in the circulation, plasmin inhibition by alpha 2AP may be down-regulated by fibrin, fibrin(ogen) fragments and Pg, but up-regulated by lipoprotein (a) in the presence of fibrin or fibrin(ogen) fragments. The lipoprotein (a)-mediated promotion of plasmin inhibition may provide an additional mechanism by which the lipoprotein impairs fibrinolysis and promotes atherosclerosis.

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The kidney is a major site of alpha(2)-antiplasmin production.

Publications

The kidney is a major site of alpha(2)-antiplasmin production.

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