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 Twitter

Kidney Week

Abstract: SA-PO024

Intracellular Complement Production and Activation in Lupus Nephritis Podocytes

Session Information

  • Bioengineering
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bioengineering

  • 300 Bioengineering

Authors

  • Satyam, Abhigyan, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Umeda, Masataka, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Bhargava, Rhea, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Tsokos, Maria, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Tsokos, George C., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
Background

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that leads to systemic autoimmunity and damage of several tissues and organs. Inflammation of the kidney is one of the most severe exhibitions of SLE that leads to lupus nephritis (LN). Podocytes are critical for the maintenance of the glomerular filtration barrier and are injured in many kidney diseases including LN. Deposition of immune complexes and activation of the complement system are well-established processes involved in the pathogenesis of LN. It has been recognized that besides the well-established pathways of complement (C) activation, C3 can be activated within the cell cytoplasm prior to its secretion. Studies have shown cleavage of C3 and C5 by proteases of the cathepsin family, thus introducing a new pathway of complement activation. Here we explored the intracellular complement production and activation in LN podocytes.

Methods

Human immortalized podocytes were cultured on engineered cell-derived decellularized matrix (DCM) coated plates. Podocytes were then exposed to IgG from patients with LN or hypoxia. Podocytes from MRLlpr and MpJ control mice were also isolated and cultured on DCM coated plates. Cathepsins and complement molecules were inhibited using nanoparticle-based targeted delivery to impede the generation of intracellular complement split products.

Results

We found that MRLlpr podocytes and human podocytes exposed to LN IgG or hypoxia displayed changes in the actin cytoskeleton, and increased levels of C3, C4, C5, C5b9, and C3 activation products. Podocytes were also noted to produce cathepsins and inhibition of cathepsins suppressed the C3 activation.

Conclusion

Podocytes exposed to IgG from patients with LN or hypoxia produce complement components as do podocytes isolated from lupus-prone mice and this leads to cell injury. Reversal of podocyte injury with inhibitors of hypoxia or complement activation limits intracellular complement activation and may prevent kidney injury in patients with LN.

Funding

  • Other NIH Support