Abstract
Inflammation related to chronic kidney disease (CKD) is an important clinical problem. We recently determined that hepatocyte nuclear factor 1α (HNF1α) was upregulated in the livers of chronic renal failure (CRF) rats—experimental model of CKD. Considering that the promoter region of gene encoding C-reactive protein (CRP) contains binding sites for HNF1α and that the loss-of-function mutation in the Hnfs1α leads to significant reduction in circulating CRP levels, we hypothesized that HNF1α can activate the Crp in CRF rats. Here, we found coordinated upregulation of genes encoding CRP, interleukin-6 (IL-6), HNF1α, and HNF4α in the livers and white adipose tissue (WAT) of CRF rats, as compared to the pair-fed and control animals. This was accompanied by elevated serum levels of CRP and IL-6. CRP and HNFs’ mRNA levels correlated positively with CRP and HNFs’ protein levels in the liver and WAT. Similar upregulation of the Crp, Il-6, and Hnfs in the liver and WAT and increased serum CRP and IL-6 concentrations were found in lipopolysaccharide (LPS)-induced systemic inflammation in rats. Moreover, silencing HNF1α in HepG2 cells by small interfering RNA led to decrease in CRP mRNA levels. Our results suggests that (a) HNFs act in concert with IL-6 in the upregulation of CRP production by the liver and WAT, leading to an increase in circulating CRP concentration in CRF rats and (b) CRF-related inflammation plays an important role in the upregulation of genes that encode HNFs and CRP in the liver and WAT of CRF rats.
Highlights
Chronic kidney disease (CKD) is a complex disorder affecting multiple human organs and systems
Our results suggest that the upregulation of genes encoding HNFs and IL-6 in the liver and white adipose tissue (WAT) of chronic renal failure (CRF) rats is closely associated with the upregulation of C-reactive protein (CRP)
The results presented above indicate that hepatocyte nuclear factor 1α (HNF1α) is involved in the regulation of CRP expression in the liver cells, leading to an increase in circulating CRP concentration in experimental CRF rats
Summary
Chronic kidney disease (CKD) is a complex disorder affecting multiple human organs and systems. The worsening of kidney function and the accumulation of waste products lead to diverse metabolic, and subsequently clinical, disturbances linked to high morbidity and mortality in CKD patients [1, 2]. Persistent low-grade inflammation is a basic feature of CKD patients. It promotes damage to kidneys and initiates and mediates destructive processes in many organs, in the cardiovascular system, leading to high morbidity and mortality rates [3, 4]. Many reports have confirmed that serum CRP and IL-6 concentrations are enhanced in CKD patients and are inversely correlated with glomerular filtration rate (eGFR) [8,9,10].
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