Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland.
Department of Pharmaceutical Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland.
Int J Mol Sci. 2023 Mar 17;24(6):5733. doi: 10.3390/ijms24065733.
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 HNF1α 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 HNF1α, we hypothesized that the upregulation of HNF1α can increase fibrinogen gene expression and consequently plasma fibrinogen concentration in the experimental model of CKD. Here, we found the coordinated upregulation of -chain fibrinogen and gene expression in the liver and elevated plasma fibrinogen concentrations in CRF rats, compared with pair-fed and control animals. Liver Aα-chain fibrinogen and HNF1α mRNAs levels correlated positively with (a) liver and plasma fibrinogen levels and (b) liver HNF1α protein levels. The positive correlation between (a) liver Aα-chain fibrinogen mRNA level, (b) liver Aα-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 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 HNF1α and Aα-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 HNF1α 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 gene expression.
慢性肾脏病（CKD）与血浆纤维蛋白原浓度升高有关。然而，CKD 患者血浆纤维蛋白原浓度升高的潜在分子机制尚未阐明。我们最近发现，HNF1α 在慢性肾衰竭（CRF）大鼠肝脏中显著上调，CRF 大鼠是 CKD 患者的实验模型。鉴于纤维蛋白原基因的启动子区域具有与 HNF1α 潜在结合的位点，我们假设 HNF1α 的上调可以增加纤维蛋白原基因的表达，从而导致 CKD 实验模型中血浆纤维蛋白原浓度升高。在这里，我们发现与配对喂养和对照动物相比，CRF 大鼠肝脏中 - 链纤维蛋白原和 基因表达协同上调，血浆纤维蛋白原浓度升高。肝 Aα-链纤维蛋白原和 HNF1α mRNA 水平与（a）肝和血浆纤维蛋白原水平以及（b）肝 HNF1α 蛋白水平呈正相关。（a）肝 Aα-链纤维蛋白原 mRNA 水平、（b）肝 Aα-链纤维蛋白原水平和（c）肾功能血清标志物之间的正相关表明纤维蛋白原基因转录与肾脏疾病的进展密切相关。小干扰 RNA（siRNA）敲低 HepG2 细胞系中的 导致纤维蛋白原 mRNA 水平降低。氯贝特是一种降低人类血浆纤维蛋白原浓度的降脂药物，可降低（a）CRF 大鼠肝脏和（b）HepG2 细胞中 HNF1α 和 Aα-链纤维蛋白原 mRNAs 水平。获得的结果表明，（a）肝脏中 HNF1α 水平升高可能在 CRF 大鼠肝脏中纤维蛋白原基因表达的上调中起重要作用，导致血浆纤维蛋白原浓度升高，纤维蛋白原是 CKD 患者心血管疾病风险相关的蛋白质，（b）贝特类药物可通过抑制 基因表达降低血浆纤维蛋白原浓度。
