IRF‐1 promotes renal fibrosis by downregulation of Klotho

Abstract

Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF‐1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF‐1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF‐1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF‐1 repressed Klotho expression by downregulation of C/EBP‐β, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor‐alpha may be an important inducement for the increase of IRF‐1 in tubular epithelial cells after UUO and genetic deletion of IRF‐1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF‐1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF‐1 may be a potential therapeutic target for CKD.

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

“…Furthermore, it was identified in trans to c. −148 (G > A) in patient five, who was also a carrier of the S102P variant and a β 0 -thalassemia mutation ( Table 3 ). We employed GeneCards and JASPAR databases [ 51 ] for the search of putative transcriptional binding sites in these two regions. Bioinformatics analysis predicted three transcriptional factors that could bind the promoter region around position −251 (KLF17, ZBTZ7B and ZNF470).…”

The nuclear factor of activated T cells 5 (NFAT5) contributes to the renal corticomedullary differences in gene expression

“…Together with STAT4, the transcriptional factor interferon regulatory factor 1 (IRF1) is also predicted to be activated. IRF1 activity is associated with cardio-renal syndrome type 4 55 and promotes renal fibrosis by reducing klotho 56 . As STAT3, IRF1 and NFKB1 are drivers of kidney fibrosis 57 , they could be involved in the kidney injury related transcriptional profile after loss of NFAT5.…”

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

“…We can make informed assumptions and infer the involvement of specific cell types which do play an active role in tissue-specific co-expression networks ( 124 ). ATM is mainly found in endothelial and epithelial cells ( 125 , 126 ), FGFR1 in fibroblasts and epithelial cells ( 57 , 58 ), FBXW7 in hepatic stellate mesenchymal, mononuclear and pulmonary epithelial stem cells ( 60 – 62 ), ESR1 in myofibroblasts and epithelial cells ( 63 , 64 ), CCND1 in renal glomerular mesangial and hepatic stellate cells ( 66 , 127 ), HIF1A in renal epithelial cells and cardiac fibroblasts ( 68 , 128 ), CEBPB in hematopoietic and renal epithelial cells ( 70 , 71 ), NAMPT in hepatic stellate and renal glomerular mesangial cells ( 72 , 129 ), IRF1 in renal epithelial cells ( 76 ), SOCS1 in hepatocytes and macrophages ( 78 ), SOCS3 in cardiac fibroblasts ( 90 ), ICAM1 in endothelial cells ( 79 ), ETS1 in hepatic stellate and renal epithelial cells ( 130 , 131 ), IL7R in hepatic stellate cells ( 82 ), MMP1 in fibroblasts ( 83 , 132 ), HNF4A in hepatocytes ( 85 ), CCL2 in fibroblasts ( 86 , 133 ), CASP1 in hepatic endothelial cells ( 87 ) and STAT1 in macrophages ( 88 , 89 ). HSP90B1 , although it has been recently reported to be implicated in fibrosis ( 92 ), the specific cell type expressing it, still, remains undetermined.…”