Tue Jul 25 2023

Perturbations in podocyte transcriptome and biological pathways induced by FSGS-associated circulating factors

CD40 and suPAR mediate podocyte injury caused by sera from FSGS patients and can be blocked by human anti-uPAR and anti-CD40 antibodies. Transcriptomic studies to compare the molecules and pathways activated in response to CD40 autoantibody from rFSGS patients (rFSGS/CD40autoAb) and suPAR identified unique inflammatory pathways associated with FSGS injury.

Background: It is known that focal segmental glomerulosclerosis (FSGS) is frequently associated with heavy proteinuria and progressive renal failure requiring dialysis or kidney transplantation. However, primary FSGS also has a ~40% risk of disease recurrence in the transplanted kidney (rFSGS). Interestingly, multiple circulating factors have been identified to contribute to the pathogenesis of primary and rFSGS, including soluble urokinase-type plasminogen activator receptor (suPAR) and patient-derived CD40 autoantibody (CD40autoAb). However, the downstream effector pathways specific to individual factors require further study. The tumor necrosis factor, TNF pathway activation by one or more circulating factors present in the sera of patients with FSGS has been supported by multiple studies.

Methods: A human in vitro model was used to study podocyte injury measured as the loss of actin stress fibers. Anti-CD40 autoantibody was isolated from FSGS patients (recurrent and non-recurrent) and control patients with ESRD due to non-FSGS-related causes. Consequently, two novel human antibodies—anti-uPAR (2G10) and anti-CD40 antibody (Bristol Meyer Squibb, 986090) were tested for their ability to rescue podocyte injury. Podocytes treated with patient-derived antibodies were transcriptionally profiled using a whole human genome microarray.

Conclusion: The study identified several novel and previously described genes associated with FSGS progression. Targeted blockade of suPAR and CD40 pathways with novel human antibodies showed inhibition of podocyte injury in FSGS.

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