ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: FR-PO703

Gnaq Deficiency Enhances Ifi202b/IFI16 and NF-kappaB Pathway in Kidney Endothelial Cell and Lupus Nephritis Pathology

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Zhang, Lu, Department of Nephrology (Fujian Provincial Clinical Research Center for Glomerular Nephritis), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
  • Shen, Jianxing, Department of Nephrology (Fujian Provincial Clinical Research Center for Glomerular Nephritis), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
  • Chen, Xing, Department of Nephrology (Fujian Provincial Clinical Research Center for Glomerular Nephritis), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
  • Shi, Guixiu, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Background

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE), the heterogeneity is still a great major challenge to study. Our previous study revealed a negative correlation between Gnaq (G protein subunit alpha q) and autoimmune diseases. As Gnaq was also relatively enriched in the kidney glomerular endothelium, in addition, Gnaq heterozygous knockout mice exhibited an aberrant glomerular endothelial phenotype. Hereon we found the role of GNAQ in LN remains unclear.

Methods

LN was induced by pristane administration in female appropriate age C57BL/6 Gnaq+/- and littermate Gnaq+/+ mice. Renal disease was assessed by the quantification of proteinuria and histologic analyses. Transcriptomic analysis was conducted on leukocytes and glomeruli obtained from Gnaq+/+ and Gnaq+/- mice for differentially expressed genes.

Results

Treatment with pristane induced diffuse proliferative LN characterized by kidney morphology and persistent albuminuria at 16 weeks follow-up in Gnaq+/- mice. Mechanistically, levels of the Interferon activation protein 202b (Ifi202b) were significantly elevated in the glomeruli when Gnaq was deficient and followed lupus. Moreover, GNAQ knockdown endothelial cell increased the expression of IFI16 (Ifi202b human ortholog) and activation of the NF-kappaB pathway, which was associated with enhanced endothelial cell adhesion. Furthermore, by transferring bone marrow from WT-Gnaq+/-, mice (WT-Gnaq+/-) developed macroproteinuria and diffuse proliferative nephritis induced by pristane when compared with other groups. Last but not the least, increased expression of IFI16 was shown to be associated with proliferative LN on human biopsy among CKDs.

Conclusion

The findings of this study reveal that Gnaq heterozygous loss mice were prone to develop proliferative nephritis by pristane induction. GNAQ acts as an inflammatory regulator in kidney endothelial cells through IFI16-NF-kappaB. The endothelial IFI16 expression level is correlated with human LN among CKDs. These findings offer valuable insights for diagnosing against LN and potential mechanisms behind GNAQ and autoimmune diseases.

Funding

  • Government Support – Non-U.S.