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