Abstract:Chronic infection with hepatitis C virus (HCV) is a major public health problem, with nearly 170 million infected individuals worldwide. Current treatment for chronic infection is a combination of pegylated IFN-α 2 and ribavirin (RBV); however, this treatment is effective in fewer than 50% of patients infected with HCV genotype 1 or 4. Recent studies identified the chemokine CXCL10 (also known as IP-10) as an important negative prognostic biomarker. Given that CXCL10 mediates chemoattraction of activated lymph… Show more
“…Also, our data indicate that TGF-b2/DPP-4/miR29s display cross-talk mechanisms in the onset of kidney fibrosis, and linagliptin-mediated inhibition of DPP-4 would diminish profibrotic signaling cross-talk in the kidney. Among human fibrotic diseases, patients with hepatitis C viral infections, the condition associated with microRNA 29 suppression, also exhibit high DPP-4 activity; such DPP-4 activity could be a potential target for combating such liver diseases (37). Further study is required to determine whether DPP-4 activity is greater in type 1 or type 2 diabetic kidney diseases, or in other fibrotic chronic and acute diseases, including kidney disease, and their association with microRNA 29s levels in humans.…”
Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2–induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.
“…Also, our data indicate that TGF-b2/DPP-4/miR29s display cross-talk mechanisms in the onset of kidney fibrosis, and linagliptin-mediated inhibition of DPP-4 would diminish profibrotic signaling cross-talk in the kidney. Among human fibrotic diseases, patients with hepatitis C viral infections, the condition associated with microRNA 29 suppression, also exhibit high DPP-4 activity; such DPP-4 activity could be a potential target for combating such liver diseases (37). Further study is required to determine whether DPP-4 activity is greater in type 1 or type 2 diabetic kidney diseases, or in other fibrotic chronic and acute diseases, including kidney disease, and their association with microRNA 29s levels in humans.…”
Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2–induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.
“…In these chronically infected individuals, HCV-specific T cells are ineffective at eradicating virus, yet are potent mediators of hepatocellular injury. Evidence presented in this issue of the JCI by Casrouge et al (4) suggests that chemokine antagonism may contribute to this inability to clear HCV infection. Their data (4) also provide an explanation as to why high levels of the chemokine CXCL10 in the plasma or serum of an HCV-infected patient portend a poor response to peg-IFN-α and ribavirin (5)(6)(7)(8).…”
Section: Immune Responses To Hepatitis C Virus (Hcv) Fail To Clear Thmentioning
confidence: 95%
“…FA is caused by mutations in one of fourteen or more genes (the so-called FA genes), whose products cooperate to ensure the repair of interstrand crosslinks that form during DNA replication (i.e., during the S phase of the cell cycle) (2). Failure to repair these lesions efficiently leads to the activation of S and G 2 cell cycle checkpoints that trigger cell cycle arrest (3,4). Failure of cells, particularly HSCs and blood cell precursors, to progress through the cell cycle has been thought to contribute to the BMF experienced by patients with FA (5).…”
“…The favorable IFNL3 variant is associated with lower ISG expression in pretreatment liver biopsies (39), and exogenous IFN-α induces a rapid antiviral state (40). Interestingly, serum levels of IFN-γ-induced protein 10 (IP-10 or CXCL10), a well-characterized marker of HCV (41) that may antagonize T cell recruitment in chronic infection (42), enhance the predictive value of the IFNL3 genotype in patients receiving dual therapy (43). In addition, the dinucleotide ss469415590 variant of IFNL4 (44), a newly identified gene upstream of IFNL3, provides an even greater prediction of impaired viral kinetics among African-Americans than rs12979860 variants of IFNL3 (44).…”
Section: Association Of Genetic Variation In Ifn-λ Genes and Hcv Recomentioning
Since the discovery of hepatitis C virus (HCV) by molecular cloning almost a quarter of a century ago, unprecedented at the time because the virus had never been grown in cell culture or detected serologically, there have been impressive strides in many facets of our understanding of the natural history of the disease, the viral life cycle, the pathogenesis, and antiviral therapy. It is apparent that the virus has developed multiple strategies to evade immune surveillance and eradication. This Review covers what we currently understand of the temporal and spatial immunological changes within the human innate and adaptive host immune responses that ultimately determine the outcomes of HCV infection.
Conflict of interest:The author has declared that no conflict of interest exists.
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