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

Background: 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 recurrence of disease in the transplanted kidney (rFSGS). 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. 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 antibody were transcriptionally profiled using whole human genome microarray.
Results: Here we show that podocyte injury caused by sera from FSGS patients is mediated by CD40 and suPAR 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.
Conclusions: We 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.
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3670/coif). MMS is a founder of technology for the assessment of kidney injury, owned by the regents, University of California. As the founder she has financial or non-financial interests in Nephrosant. JR reports that he receives consulting fees from Reata, Novateur Ventures, Walden Biosciences, Biomarin, Astellas, Massachusetts General Hospital, Genentech, Up to Date, Merck, Insceptionsci, GL, Visterra, Aclipse and MantraBio. JR also has several patents: US20110212083-Role of soluble uPAR in the Pathogenesis of Proteinuric Kidney Disease, S9867923-Reducing Solucble Rokinase Receptor in the Circulation, JP2016530510-Non-Glycoslyated suPAR Biomarkers and Uses thereof, US20160296592-Methods/Compositions for the Treatment of Proteinuric Diseases, US9144594-Dynamin Mediated Diseases and US8809386-Dynamin Ring Stabilizers. JR is on Scientific advisory board of Walden Biosciences and has stocks/stock options at Walden Biosciences and Aclipse. The other authors have no conflicts of interest to declare.
(2023 Annals of Translational Medicine. All rights reserved.)