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Zinc-?2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart.

ABSTRACT: Zinc-?2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombinant AZGP1. Exposure of AZGP1-deficient mice to cardiac stress by thoracic aortic constriction revealed that antifibrotic effects were not restricted to the kidney but were cardioprotective. In vitro, recombinant AZGP1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-? signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-? signaling in fibroblasts. Taken together, these findings indicate a novel role for AZGP1 as a negative regulator of fibrosis progression, suggesting that recombinant AZGP1 may have translational effect for treating fibrotic disease.

SUBMITTER: Sorensen-Zender I

PROVIDER: S-EPMC4625663 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart.

Sörensen-Zender Inga I Bhayana Sagar S Susnik Nathan N Rolli Veronique V Batkai Sandor S Baisantry Arpita A Bahram Siamak S Sen Payel P Teng Beina B Lindner Robert R Schiffer Mario M Thum Thomas T Melk Anette A Haller Hermann H Schmitt Roland R

Journal of the American Society of Nephrology : JASN 20150318 11

Zinc-α2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombina ...[more]

PMID: 25788525

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Project description:Objectives: To explore serum zinc-α2-glycoprotein (ZAG) changes in patients with or without premature coronary artery disease (PCAD) and its association with several cardiovascular risk factors. Methods: A total of 3,364 patients who were undergone coronary angiography in Peking Union Medical College Hospital were screened. According to the degree of coronary artery stenosis, the number of 364 patients with PCAD (age <55 years in males and <65 years in females) and 126 age and gender matched patients without premature coronary artery disease (NPCAD) were recruited in our present study. In addition, 182 age and gender matched healthy controls were also enrolled. Serum ZAG levels were determined by enzyme-linked immunosorbent assay (ELISA) method. Results: Serum ZAG were significantly lower in the PCAD (8.03 ± 1.01 vs. 8.78 ± 1.89 μg/mL, p < 0.05) and NPCAD groups (8.28 ± 1.61 vs. 8.78 ± 1.89 μg/mL, p < 0.05), respectively, when compared with the controls. Multiple regression analysis showed that PCAD was independently associated with serum ZAG levels (B = -0.289, p = 0.002). The probability of PCAD in subjects with low tertile ZAG levels was 2.48-fold higher than those with high tertile levels after adjusting for other confounders [OR = 3.476, 95% CI 1.387-8.711, p = 0.008]. This phenomenon was more likely to be observed in male subjects with BMI <24 kg/m2. The receiver operating curve (ROC) analysis showed a weak diagnostic performance of serum ZAG for PCAD (AUC = 0.659, 95% CI 0.612-0.705, p < 0.05). At the cutoff value of 7.955 μg/mL serum ZAG, the sensitivity and specificity for differentiating patients with PCAD from controls were 50.5 and 78.0%, respectively. The combination of ZAG with other clinical variables including age, gender, BMI, SBP, FBG, TC, HDL-C, Cr, and Urea had significantly improved the diagnosis accuracy with a sensitivity of 82.6%, a specificity of 95.0%, and AUC of 0.957 (95% CI, 0.940-0.975, p < 0.05). Conclusion: Serum ZAG levels were firstly found to be decreased in Chinese PCAD patients. Subjects with lower ZAG levels were more likely to have PCAD, especially for male subjects with BMI <24 kg/m2. ZAG might be the potential diagnostic biomarkers for PCAD patients, and the combination of ZAG and clinical variables had higher discriminative performance.

Project description:Graves' ophthalmopathy (GO) is a common orbital disease that threatens visual function and appearance. Orbital fibroblasts (OFs) are considered key target and effector cells in GO. In addition, hyaluronan (HA) production, inflammation, and orbital fibrosis are intimately linked to the pathogenesis of GO. In this study, we explored the therapeutic effects of dihydroartemisinin (DHA), an antimalarial drug, on GO-derived, primary OFs. CCK8 and EdU assays were applied to evaluate the antiproliferative effect of DHA on OFs. Wound healing assays were conducted to assess OF migration capacity, while qRT-PCR, western blotting, ELISA, and immunofluorescence were used to determine the expression of fibrosis-related and pro-inflammatory markers in these cells. Moreover, RNA sequencing was conducted to identify differentially expressed genes (DEGs) in DHA-treated OFs, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs was performed to explore potential mechanisms mediating the antifibrotic effect of DHA on GO-derived OFs. Results showed that DHA dose-dependently inhibited OF proliferation and downregulated, at the mRNA and protein levels, TGF-β1-induced expression of fibrosis markers, including alpha smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF). Furthermore, DHA inhibited TGF-β1 induced phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3), which suggested that DHA exerted antifibrotic effects via suppression of the ERK and STAT3 signaling pathways. In addition, DHA suppressed the expression of pro-inflammatory cytokines and chemokines, including IL-6, IL-8, CXCL-1, MCP-1, and ICAM-1, and attenuated HA production induced by IL-1β in GO-derived OFs. In conclusion, our study provides first-time evidence that DHA may significantly alleviate pathogenic manifestations of GO by inhibiting proliferation, fibrosis- and inflammation-related gene expression, and HA production in OFs. These data suggest that DHA may be a promising candidate drug for treatment of GO.

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Zinc-?2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart.

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Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart.

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