Kidney Week

Abstract: SA-PO731

mTOR Inhibition: A Novel Regulator of Soluble CD89 Activity via the Mesangial Transferrin Receptor and Its Therapeutic Potential in IgA Nephropathy

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Alexandra, Cambier, Research Centre Sainte Justine Hospital, Montreal, Quebec, Canada

Cambier Alexandra, MD, PhD

• Da Silva, Jennifer, Inserm U1149, Paris ile de France, Paris, France

Jennifer Da Silva

• Bex, Julie, Inserm U1149, Paris ile de France, Paris, France

Julie Bex

• Sannier, Aurelie, Inserm U1149, Paris ile de France, Paris, France

Aurelie Sannier, MD, PhD

• Badie, Amandine, Research Centre Sainte Justine Hospital, Montreal, Quebec, Canada

Amandine Badie, PhD

• Monteiro, Renato C., Inserm U1149, Paris ile de France, Paris, France

Renato C. Monteiro, MD, PhD

Background

IgA nephropathy (IgAN) is the predominant primary glomerulonephritis worlwide. We have recently shown that soluble IgA receptor CD89 induces mesangial cell proliferation via the PI3K/Akt/mTOR axis (Cambier, Kidney Int 2022). Transferrin receptor (TfR), an IgA1 receptor overexpressed in mesangium, is associated with IgAN progression (Tamouza, Kidney Int 2012). sCD89 binds also to TfR (Berthelot, J Exp Med 2012). As mTOR is involved in sCD89-TfR signaling, we explore its inhibitor, the everolimus, in a IgAN model, the α1^KICD89^Tg mouse, that express human IgA1 and CD89. Single-cell kidney biopsy techniques were used to delve TfR1 and mTOR expression in mesangial cells from IgAN patients.

Methods

20 adult α1^KICD89^Tg and 6 young rCD89-injected α1^KI mice constituted two groups. Treated arms received everolimus (2 mg/kg) for 8 weeks or 4 weeks, respectively, while the control arms underwent a placebo water. Weekly urine collections monitored proteinuria and mice were sacrificed for renal function, immune complex analysis, and histological examination. PI3K/Akt/mTOR activation under sCD89 stimulation was studied with human mesangial cells. Single cell analysis were performed to quantify mTOR and TfR1 expression in 5 patient kidney biopsy and 1 healthy kidney tissue.

Results

Everolimus treatment showed a reduction in mesangial TfR expression, IgA1 and C3 deposits in kidneys of both groups (p<0.001, respectively). It also decreased cell proliferation, as indicated by Ki67 staining in glomeruli (p<0.05). This treatment led to decreased proteinuria (p<0.05). Levels of immune complexes (sCD89-IgA1, IgG-IgA1) were impaired by everolimus treatment. Rec sCD89 induced activation of PI3K/Akt/mTOR pathway in human mesangial cells. Using single cells from kidney biopsies we found overexpression of TfR1 and mTOR in mesangial cells from IgAN patient biopsies but not in healthy kidney.

Conclusion

mTOR inhibitor prevents and treats IgAN in a pre-clinical model. These results open new avenues for future clinical trials in IgAN.

Funding

• Government Support – Non-U.S.