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1.
Cell Commun Signal ; 22(1): 220, 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38589923

ABSTRACT

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.


Subject(s)
Lupus Nephritis , MicroRNAs , Humans , Mice , Animals , Lupus Nephritis/genetics , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/genetics , Toll-Like Receptor 8/metabolism , Kidney/metabolism , Mice, Transgenic , MicroRNAs/genetics
2.
Free Radic Biol Med ; 67: 91-102, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24161443

ABSTRACT

Aberrant regulation in oxidative stress, fibrogenesis, and the epithelial-mesenchymal transition (EMT) in renal cells under hyperglycemic conditions contributes significantly to the onset and progression of diabetic nephropathy. The mechanisms underlying these hyperglycemia-induced dysregulations, however, have not been clearly elucidated. Herein, we report that aldose reductase is capable of regulating the expression of miR-200a-3p/141-3p negatively in renal mesangial cells. MiR-200a-3p/141-3p, in turn, act to target Keap1, Tgfß2, fibronectin, and Zeb2 directly and regulate Tgfß1 and Nrf2 indirectly under high-glucose conditions, resulting in profound dysregulations in Keap1-Nrf2, Tgfß1/2, and Zeb1/2 signaling. In vivo in streptozotocin-induced diabetic mice, we found that aldose reductase deficiency caused significant elevations in miR-200a-3p/141-3p in the renal cortex, which were accompanied by a significant downregulation of Keap1, Tgfß1/2, and fibronectin but significant upregulation of Nrf2. Moreover, in vivo administration of inhibitors of miR-200a-3p in diabetic animals significantly exacerbated cortical and glomerular fibrogenesis and increased urinary albumin excretion, tightly linking dysregulated miR-200a-3p with the development of diabetic nephropathy. Collectively, our results reveal a novel mechanism whereby hyperglycemia induces aldose reductase to regulate renal expression of miR-200a-3p/141-3p to coordinately control hyperglycemia-induced renal oxidative stress, fibrogenesis, and the EMT. Our novel findings also suggest that inhibition of aldose reductase and in vivo renal cortical restoration of miR-200a-3p/141-3p or their combination are very promising avenues for the development of therapeutic strategies or drugs against diabetic nephropathy.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Aldehyde Reductase/genetics , Cytoskeletal Proteins/genetics , Kidney Cortex/metabolism , Mesangial Cells/metabolism , MicroRNAs/genetics , Signal Transduction/genetics , Adaptor Proteins, Signal Transducing/metabolism , Aldehyde Reductase/metabolism , Animals , Cell Line , Cytoskeletal Proteins/metabolism , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Gene Expression Regulation , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Kelch-Like ECH-Associated Protein 1 , Kidney Cortex/pathology , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Male , Mesangial Cells/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , MicroRNAs/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta2/genetics , Transforming Growth Factor beta2/metabolism , Zinc Finger E-box Binding Homeobox 2 , Zinc Finger E-box-Binding Homeobox 1
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