EXTRAHEPATIC EXPRESSION AND REGULATION OF PROTEIN-C IN THE MOUSE

Activated protein C (APC) acts as an anticoagulant by inhibiting coagu lation factors Va and VIIIa. Although the liver appears to be the prim ary site of protein C (PC) synthesis, the demonstration that other com ponents of this system are produced extrahepatically raises the possib ility that PC itself is synthesized in other tissues. We therefore use d quantitative reverse transcription-polymerase chain reaction, in in situ hybridization, and immunohistochemistry to screen various murine tissues for PC expression, Relatively high levels of PC mRNA were dete cted in the kidney (35% of liver) and testis (22% of liver). PC mRNA a nd antigen were demonstrated in. tubular epithelial cells in the renal cortex, in spermatogenic cells in the testis, and in epithelial cells in the epididymis. Low but significant levels of PC mRNA were detecte d in the epididymis (1.7% of the level in liver), brain (1.1% of liver ), and lung (0.8% of liver). PC antigen was demonstrated in. bronchial epithelial cells in the lung, in pyramidal neurons in the cerebrum, a nd in Purkinje cells in the cerebellum. The extrahepatic expression of PC mRNA (ie, in the kidney) was significantly decreased in mice with renal disease (eg, in MRL lpr/lpr mice with autoimmune lupus nephritis , in db/db mice with diabetic nephropathy, and in endotoxin-treated mi ce with acute renal injury). The decreased renal expression of PC may contribute to the increased procoagulant potential of the kidney durin g septic and inflammatory processes and to the progression of kidney d isease associated with these conditions.