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Abstract: TH-PO1088

Identification of Podocyte Secreted Proteins That Drive Parietal Epithelial Cell Proliferation in a Murine Model of Proliferative Glomerulopathy

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology


  • Pace, Jesse Alexander, Stony Brook Medicine, Stony Brook, New York, United States
  • Guo, Yiqing, Stony Brook Medicine, Stony Brook, New York, United States
  • Estrada, Chelsea C., Stony Brook Medicine, Stony Brook, New York, United States
  • Mallipattu, Sandeep K., Stony Brook Medicine, Stony Brook, New York, United States

Podocyte injury contributing to parietal epithelial cell (PEC) proliferation is a dominant histologic feature in both rapidly progressive glomerulonephritis and subtypes of focal segmental glomerulosclerosis (FSGS), however factors mediating this cross-talk remain unclear. We recently showed that podocyte-specific loss of Krüppel-like factor 4 (Klf4), a zinc-finger transcription factor, activates STAT3 signaling leading to mitotic catastrophe in podocytes and eventual FSGS, while triggering PEC proliferation in mice. We utilized this model to identify novel factors secreted by the injured podocyte that drive PEC proliferation.


Initially, RNA-seq was conducted on glomeruli isolated from mice with podocyte-specific deletion of Klf4 (Klf4ΔPOD) and controls (Klf4fl/fl). Since our previously reported data demonstrate that conditioned media (CM) isolated from cultured human podocytes with KLF4 knockdown (KLF4-shRNA) triggers PEC proliferation, we performed quantitative mass spectrometry (iTRAQ) on CM from KLF4-shRNA and EV-shRNA cultured human podocytes from day 1 to 3 of differentiation. Subsequent differential expression and ChIP-enrichment analysis was performed to identify STAT3-dependent and independent secreted factors by the podocyte that drive PEC proliferation.


Pathway analysis revealed that 421 genes were upregulated in Klf4ΔPOD glomeruli and were related to ECM organization and focal adhesion, whereas 179 identified downregulated genes were enriched for genes critical to podocyte protein-protein interactions, actin cytoskeleton, and cell differentiation. Proteins upregulated in KLF4-shRNA as compared to EV-shRNA CM were involved in similar pathways. These differentially expressed transcripts from RNA-seq were cross-matched with upregulated proteins from iTRAQ to identify factors that drive PEC proliferation. Published ChIP-seq datasets were used to identify top candidates containing STAT3 binding sites (PAI-1 and CYR61) and those without (PRSS23 and S100A6). These transcripts were then validated by qPCR in Klf4ΔPOD treated with STAT3 inhibitor, S3I-201.


Using a model of proliferative glomerulopathy (podocyte-specific Klf4 knockdown), we identified novel signaling molecules secreted by the injured podocyte that might drive aberrant PEC proliferation.


  • NIDDK Support