Hepatocyte Nuclear Factor-1a Increases Fibrinogen Gene Expression in Liver and Plasma Fibrinogen Concentration in Rats with Experimental Chronic Renal Failure

Chronic kidney disease (CKD) is associated with elevated plasma fibrinogen concentration. However, the underlying molecular mechanism for elevated plasma fibrinogen concentration in CKD patients has not yet been clarified. We recently found that HNF1a was significantly upregulated in the liver of chronic renal failure (CRF) rats, an experimental model of CKD in patients. Given that the promoter region of the fibrinogen gene possesses potential binding sites for HNF1a, we hypothesized that the upregulation of HNF1a can increase fibrinogen gene expression and consequently plasma fibrinogen concentration in the experimental model of CKD. Here, we found the coordinated upregulation of Aa-chain fibrinogen and Hnfa gene expression in the liver and elevated plasma fibrinogen concentrations in CRF rats, compared with pair-fed and control animals. Liver Aa-chain fibrinogen and HNF1a mRNAs levels correlated positively with (a) liver and plasma fibrinogen levels and (b) liver HNF1a protein levels. The positive correlation between (a) liver Aa-chain fibrinogen mRNA level, (b) liver Aa-chain fibrinogen level, and (c) serum markers of renal function suggest that fibrinogen gene transcription is closely related to the progression of kidney disease. Knockdown of Hnfa in the HepG2 cell line by small interfering RNA (siRNA) led to a decrease in fibrinogen mRNA levels. Clofibrate, an anti-lipidemic drug that reduces plasma fibrinogen concentration in humans, decreased both HNF1a and Aa-chain fibrinogen mRNAs levels in (a) the liver of CRF rats and (b) HepG2 cells. The obtained results suggest that (a) an elevated level of liver HNF1a can play an important role in the upregulation of fibrinogen gene expression in the liver of CRF rats, leading to an elevated concentration of plasma fibrinogen, a protein related to the risk of cardiovascular disease in CKD patients, and (b) fibrates can decrease plasma fibrinogen concentration through inhibition of HNF1a gene expression.

Automated summary

Chronic kidney disease (CKD) is associated with elevated plasma fibrinogen concentration, with HNF1a gene upregulation leading to increased fibrinogen gene expression. The mRNA levels of liver fibrinogen and HNF1a are closely related to the progression of kidney disease. Decreasing HNF1a gene expression can reduce plasma fibrinogen concentration.