Coordinate augmentation in expression of genes encoding transcription factors and liver secretory proteins in hypo-oncotic states

Background In the nephrotic syndrome (NS) proteins of intermediate size (40 to 200 kD) are lost into the urine resulting in a decrease in plasma album in concentration and as a consequence a reduction in plasma colloid osmotic pressure (pi). Plasma pi has also been reported to be reduced in the condi tion of hereditary analbuminemia. The liver, in an apparent compensatory re sponse, increases synthesis of a group of secreted proteins defending plasm a pi. Regulation of several of these proteins, including both positive and negative acute phase proteins, is at the transcriptional level. This is the only known condition in which transcription of both positive and negative acute phase proteins (APPs) are increased simultaneously. The specific tran scription factor(s) that might regulate this cascade is not defined. Methods. RNA was extracted from livers of 5 rats with hereditary analbumine mia (the Nagase analbuminemic rat, NAR), 5 rats with NS induced by adriamyc in (Adria), 5 rats with NS caused by passive Heymann nephritis (NS) and 5 c ontrol animals. The concentrations of mRNAs encoding four secreted proteins (albumin, transferrin, fibrinogen, and apo A-1), five transcription factor s, early growth response factor 1 (EGRF-1), HNF-4, NGFI-C, EGR3, and Krox20 relative to two housekeeping genes, beta actin and GAPDH were determined s imultaneously using kinetic reverse transcriptase polymerase chain methodol ogy (kRT-PCR). Results. The levels of all mRNAs encoding secreted proteins except for albu min (which was reduced in NAR) were increased in NS and NAR and correlated significantly with one another. mRNA encoding EGRF 1 was increased fivefold in NS and NAR, and correlated significantly with mRNAs encoding Apo A-1, t ransferrin and albumin in the two NS groups. HNF-4 mRNA was increased appro ximately twofold in both NS groups and correlated with albumin (R = 0.881, P < 0.001), transferrin (R = 0.563, P = 0.012) and apo A-1 (R = 0.644, P = 0.003). While fibrinogen mRNA correlated with that of each of the other sec reted proteins, it did not correlate with either HNF-4 or EGRF-1 mRNA. Krox 20, EGR3 and NGF1C were expressed at nearly undetectable levels. Conclusions. The hepatic response in conditions characterized by reduced pl asma pi include increased levels of mRNAs encoding a group of secreted prot eins, including the negative APPs albumin, transferrin and apo A-1, and the positive APP fibrinogen. Levels of mRNAs encoding negative APPs and fibrin ogen correlate with one another, suggesting that they are coordinately cont rolled. Both EGRF-1 and HNF-4 may regulate the expression of the negative A PPs, which have increased transcription in hypo-oncotic states.