Diabetes nephropathy (DN) is characterized by abnormal interactions between kidney‐infiltrating macrophages and glomerular mesangial cells. Recently, a novel cell‐cell communication mediated by exosomes has gained attention. Exosomes are membrane‐bound vesicles that contain a variety of molecules such as proteins, lipids, DNA, mRNA, and microRNAs. Exosomes play an important role in the pathogenesis of DN. In this study, we show that high glucose (HG) led to increased excretion of exosomes from macrophages. Mesangial cells took up exosomes in vitro, which resulted in the activation and proliferation of mesangial cells and the secretion of extracellular matrix and inflammatory cytokines. In addition, C57BL/6 mice injected with exosomes from HG‐treated macrophages showed morphologic and functional changes. We then showed that exosomes from HG‐treated TGF‐β1 knockdown macrophages induced less extracellular matrix and fewer inflammatory factors in mesangial cells compared with vector control. Our findings suggest that TGF‐β1 mRNA in exosomes serves a role between macrophages and mesangial cells by activating the TGF‐β1/ mothers against decapentaplegic homolog 3 pathway.—Zhu, Q.‐J., Zhu, M., Xu, M.‐X., Meng, X.‐M., Wu, Y.‐G. Exosomes from high glucose‐treated macrophages activate glomerular mesangial cells via TGF‐β1/Smad3 pathway in vivo and in vitro. FASEB J. 33, 9279–9290 (2019). http://www.fasebj.org

Purpose: To date, the prevalence and prognostic role of coronary artery calcification (CAC) in patients with chronic kidney disease (CKD) have been investigated in several studies, but have yielded conflicting results. The aim of this meta-analysis is to derive a more precise estimation of CAC prevalence in CKD patients and its association with cardiovascular events and mortality. Methods: The relevant literature was identified and evaluated from inception until July 2018 through multiple search strategies on PubMed, Embase, and Web of Science. Cross-sectional or cohort (baseline data) studies reporting CAC prevalence were included. Data extracted from eligible studies were used to calculate effect estimates (ESs) and 95% confidence intervals (95%CI). We searched databases for observational studies that explored baseline CAC and subsequent cardiovascular or all-cause mortality risk in CKD patients. Results: The meta-analysis included 47 studies; 38 of these were included in the final analysis of CAC prevalence. The pooled prevalence of CAC in random effect model was 60% (95%CI 53–68%). CAC was positively associated with an increased risk of all-cause mortality (hazard ratio [HR] 3.44; 95%CI 2.40–4.94), cardiovascular mortality (HR 3.87; 95%CI 2.06–7.26), and cardiovascular events (HR 2.09; 95%CI 1.19–3.67), when comparing individuals in the top CAC score group to those in the bottom CAC score group. Conclusions: The pooled prevalence of CAC is highly prevalent. CAC is independently associated with all-cause and cardiovascular mortality risk as well as cardiovascular events among CKD patients. In view of the high heterogeneity, larger clinical trials are still needed.

Objective and designSeveral works in the setting of early experimental diabetic nephropathy using anti-inflammatory drugs, such as the calcineurin inhibitor FK506, have shown prevention of the development or amelioration of renal injury including proteinuria. The exact mechanisms by which anti-inflammatory drugs lower the albuminuria have not been still clarified well.MaterialsThe diabetic rats were induced by using streptozotocin.TreatmentThe diabetic rats were subjected to oral FK506 treatment at a dose of 0.5 or 1.0 mg/kg daily for 4 weeks.MethodsRenal histology for the ultrastructural evaluation was determined by electron microscope, followed by analyses of renal nephrin and podocin and detection of renal iNOS+ macrophages and NF-κB-p-p65+.ResultsElevated 24-h urinary albumin excretion rate was markedly attenuated by FK506 treatment. In diabetic model rats, FK506 treatment at a dose of 0.5 or 1.0 mg/kg significantly increased the expression of nephrin and podocin when compared to control. As expected, rats in control diabetic group had an increase in GBM thickening and foot process effacement when compared to normal rats; increased GBM thickening and foot process effacement were ameliorated by FK506 treatment with 0.5 and 1.0 mg/kg. Histologically, there was marked accumulation of ED-1+cells (macrophages) in diabetic kidneys, and FK506 treatment failed to inhibit it. In contrast, FK506 treatment at 0.5 and 1.0 mg/kg doses significantly inhibited the elevated ED-1+/iNOS+ cells in the kidneys of diabetic rats. ED-1+/NF-κB-p-p65+ cells were significantly increased in positive diabetic kidneys compared to those of normal rats. FK506 treatment at 0.5 and 1.0 mg/kg significantly attenuated the elevated ED-1+/NF-κB-p-p65+ cells in diabetic kidneys. Additionally, a positive correlation was observed between ED-1+/iNOS+ cells and albuminuria (r = 0.87, p < 0.05). Likewise, ED-1+/iNOS+ cells were correlated negatively with both nephrin and podocin protein (r = −0.70, p < 0.05; r = −0.68, p < 0.05, respectively).ConclusionOur results show that FK506 not only upregulates expression of nephrin and podocin but also inhibits macrophage activation to protect against podocyte injury.

Objective and design Macrophages exhibit strong phenotypic plasticity and can mediate renal inflammation by polarizing into an M1 phenotype. They play a pivotal role in diabetic nephropathy (DN). Here, we have investigated the regulatory role of transforming growth factor β-activated kinase 1-binding protein 1 (TAB1) in glycolysis and activation of macrophages during DN. Methods TAB1 was inhibited using siRNA in high glucose (HG)-stimulated bone marrow-derived macrophages (BMMs) and lentiviral vector-mediated TAB1 knockdown was used in streptozotocin (STZ)-induced diabetic mice. Western blotting, flow cytometry, qRT-PCR, ELISA, PAS staining and immunohistochemical staining were used for assessment of TAB1/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α), iNOS, glycolysis, inflammation and the clinical and pathological manifestations of diabetic nephropathy. Results We found that TAB1/NF-κB/HIF-1α, iNOS and glycolysis were up-regulated in BMMs under HG conditions, leading to release of further inflammatory factors, Downregulation of TAB1 could inhibit glycolysis/polarization of macrophages and inflammation in vivo and in vitro. Furthermore, albuminuria, the tubulointerstitial damage index and glomerular mesangial expansion index of STZ-induced diabetic nephropathy mice were decreased by TAB1 knockdown. Conclusions Our results suggest that the TAB1/NF-κB/HIF-1α signaling pathway regulates glycolysis and activation of macrophages in DN.

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