Search

• GDF-15 expression was increased in response to high-glucose stimulation. • Overexpression of GDF-15 can inhibit activation of NF-κB. • GDF-15 mediates nuclear translocation of NF-κB through IKK and IκB. • GDF-15 mediates the expression of NEDD4L. • NEDD4L is involved in GDF-15 mediated inhibition of the NF-κB signaling pathway. Podocyte inflammatory injury has been indicated to play a pivotal role in the occurrence and development of diabetic nephropathy (DN). However, the pathogenesis of inflammation remains unclear. Recent researches have shown that GDF-15, a member of the transforming growth factor-β superfamily, were elevated under pathological conditions, such as myocardial ischemia, cancer, as well as inflammation. Here, we demonstrated that GDF-15 could alleviate podocyte inflammatory injury by modulating the NF-κB pathway. GDF-15 and other pro-inflammatory factors, such as TNF-α, IL-1β, and IL-6 were upregulated in the serum of HFD/STZ rat models. GDF-15 was also elevated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes. The silence of GDF-15 in HG-stimulated podocytes further augmented inflammation and podocyte injury, while overexpression of GDF-15 significantly reduced the inflammatory response in podocytes. Mechanistically, we demonstrated that GDF-15 could inhibit the nuclear translocation of NF-κB through IKK and IκBα by interaction with ubiquitin ligase NEDD4L. Taken together, our data suggested a protective mechanism of elevated GDF-15 in DN through obstruction of ubiquitin degradation of IKK by inhibiting NEDD4L expression, thus decreasing the activation of NF-κB and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN. [ABSTRACT FROM AUTHOR]

Highlights: [•] TAK1 is a central component of NF-κB and MAPK signaling pathways. [•] TAK1 activation is tightly regulated by multiple modifications. [•] TAK1 functions as a negative regulator in neutrophils. [•] TAK1 plays an important role in inflammation and cancer development. [Copyright &y& Elsevier]

• miR-181d-5p expression was downregulated in PBMCs of LN patients and MRL/lpr mice. • miR-181d-5p can directly target binding to MAPK8. • Overexpression of miR-181d-5p inhibited the phosphorylation of p38 and p44/42 in the THP-1 cells. • Overexpression of miR-181d-5p elevated THP-1 cell viability and decreased the inflammatory response. • Overexpression of miR-181d-5p decreased antinuclear antibodies and fibrosis levels in MRL/lpr mice. Lupus nephritis (LN) is a common immune disease. The microRNA (miR)-181d-5p is a potential target for treating kidney injury. However, the therapeutic role of miR-181d-5p in LN has not been investigated. This study aimed to investigate the role of miR-181d-5p in targeting mitogen-activated protein kinase 8 (MAPK8) and stimulating the MAPK signaling pathway in LN. RT-qPCR was performed to identify the variations in miR-181d-5p expression in peripheral blood mononuclear cells (PBMCs) obtained from 42 LN patients, 30 healthy individuals, 6 MRL/lpr mice and 6 C57BL/6 mice. Western blot was used to detect the effect of miR-181d-5p on the MAPK signaling pathway in THP-1 cells and MRL/lpr mice. Enzyme-linked immunosorbent assay (ELISA) was utilized to detect the effect of miR-181d-5p on antinuclear antibodies and inflammatory factors. A dual-luciferase reporter assay was used to verify whether miR-181d-5p directly targets MAPK8. Flow cytometry was performed to evaluate apoptosis rates in transfected THP-1 cells. miR-181d-5p expression was downregulated in PBMCs of LN patients (P < 0.01) and MRL/lpr mice (P < 0.05). A dual luciferase reporter assay demonstrated that miR-181d-5p inhibits MAPK8 (P < 0.01). Overexpression of miR-181d-5p inhibited the phosphorylation of p38 (P < 0.001) and p44/42 (P < 0.01). Moreover, miR-181d-5p decreased the apoptosis rate of THP-1 cells (P < 0.001), and reduced the secretion of IL-6 (P < 0.01) and TNF-α (P < 0.01). Furthermore, overexpression of miR-181d-5p decreased anti-dsDNA antibody (P < 0.05), anti-Sm antibody (P < 0.01), and fibrosis levels in MRL/lpr mice. Upregulation of miR-181d-5p showed anti-inflammatory and anti-apoptotic effects on THP-1 cells in vitro and kidney injury in vivo. These effects were achieved by miR-181d-5p targeting MAPK8 to inhibit phosphorylation of p38 and p44/42. These results may offer new insights for improving therapeutic strategies against lupus nephritis. [ABSTRACT FROM AUTHOR]

[Display omitted] • ∼85 nm spaced nanorods array timely switches macrophages from M1 to M2 phenotype. • Interrod spacing switches MΦs to M2 phenotype via the FN-integrin β1 -Akt1 pathway. • M2 cytokines enhanced by arrays facilitate osteogenesis via BMP2-TGF-SMAD pathway. Osseointegration is initiated by immune cell-derived inflammatory responses to the surfaces of implanted materials. However, the bio-molecular mechanisms by which nanotopographic features of implant surfaces immunomodulate osseointegration remain to be clarified. To this end, herein, three kinds of TiO 2 nanorod-like arrays on Ti with the interrod spacing of ∼0, 45 and 85 nm, termed as S0, S45 and S85, respectively, were hydrothermally grown, and their actions on the polarization of macrophages (MΦs) and MΦs-mediated contact osteogenesis of bone marrow-derived mesenchymal stromal cells (BMSCs) were explored, especially the involved signaling pathways. Compared to pure Ti (namely P-Ti), the nanorods-arrayed Ti activated FG-integrin α M β 2 -IKK-NF-κB signaling pathway in the adhered MΦs at initial 6 h while FN-integrin α 5 β 1 -PI3K-Akt1 pathway since 24 h, accelerating the transition of MΦs from pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. With the cytokines secreted by M2 cells, the coatings activated the BMP2-TGFβ1-SMAD signaling pathway to enhance osteogenic differentiation of the recruited BMSCs in vitro. Also, the nanorods-coated Ti induced a proper immune microenvironment and accelerated bone apposition in rabbit tibia marrow cavities in vivo. Furthermore, owing to the favorable capacity of osteoimmunomodulation, the ∼85 nm spaced nanorods-arrayed coating exhibited satisfactorily in orchestrating osteogenic differentiation in vitro and in vivo. This work provides insights into nanotopographic features of implant surfaces immunomodulating contact osteogenesis. [ABSTRACT FROM AUTHOR]

Although our recent studies have demonstrated that NOD2 is one of the critical components of a signal transduction pathway that links renal injury to inflammation in diabetic nephropathy (DN), the regulatory mechanisms for NOD2 expression under hyperglycemia have not yet been elucidated. Considering that NOD2 mRNA from different species bears a long 3′-UTR with various AU-rich elements, the present study was designed to investigate the potential contribution of the RNA-binding protein human antigen R (HuR) on the posttranscriptional regulation of NOD2 expression. In this study, we first found upregulation of HuR in the kidney from DN subjects, which was correlated with proteinuria, indicating a role for HuR in the pathogenesis of DN. In vitro, high glucose (HG) induced a distinct increase in cytoplasmic HuR in rat glomerular mesangial cells. By RNA EMSA, we found that HuR bound to the 3′-UTR of NOD2, and HuR silencing reduced HG-induced NOD2 expression and mRNA stability. Mechanistically, we further found that NADPH oxidase-mediated redox signaling contributed to the expression and translocation of HuR and NOD2 mRNA stability. Finally, we evaluated the role of HuR showing that in vivo gene silencing of HuR by intrarenal lentiviral gene delivery ameliorated renal injury as well as reducing NOD2 expression in diabetic rats. Collectively, our studies demonstrate that HuR acts as a key posttranscriptional regulator of NOD2 expression, suggesting that targeting of HuR–NOD2 signaling might be crucial for the treatment of DN. [ABSTRACT FROM AUTHOR]