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Abstract: TH-PO532

Elevated Levels of IL-6 in IgA Nephropathy Patients Are Induced by an Epigenetically Driven Mechanism Modulated by Viral and Bacterial RNA

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Sallustio, Fabio, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Picerno, Angela, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Cimmarusti, Maria Teresa, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Montenegro, Francesca, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Stasi, Alessandra, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Pesce, Francesco, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Di leo, Vincenzo, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
Background

Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis characterized by the presence of IgA immune complexes in the glomeruli. Newly, the role of IL-6 in pathogenesis is becoming increasingly important but reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA.

Methods

Total RNA were isolated from PBMCs of IgAN patients, transplanted IgAN patients (TP-IgAN), non-IgAN transplanted patients (TP) and healthy subjects (HS). VTRNA2-1, CREB and PKR transcripts were evaluated by RT-PCR. Total and phosphorylated PKR, CREB and Il-6 proteins were evaluated by ELISA. Poly (I:C), a synthetic analogue of dsRNA, and Pfizer-BioNTech COVID-19 vaccine were used to transfect patient PBMCs. PKR inhibitor imoxin (C16) 1 µM was used to stimulate patient PBMCs.

Results

Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non-IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain caused the activation of CREB by PKR, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, both in IgAN and in TP-IgAN patients. PKR is normally activated by bacterial and viral RNA and we found that both the RNA poly(I:C) and the COVID-19 vaccine stimulation significantly increase the IL-6 levels in PBMCs from HS but had an opposite effect in those from IgAN patients.

Conclusion

In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients.

Funding

  • Private Foundation Support