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Abstract: FR-OR067

Krüppel-Like Factor 4 Is a Negative Regulator of Aberrant Glomerular Epithelial Cell Proliferation

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology


  • Estrada, Chelsea C., Stony Brook Medicine, Stony Brook, New York, United States
  • Guo, Yiqing, Stony Brook Medicine, Stony Brook, New York, United States
  • Paladugu, Praharshasai, Stony Brook Medicine, Stony Brook, New York, United States
  • Cardona, Stephanie, Stony Brook Medicine, Stony Brook, New York, United States
  • Revelo Penafiel, Monica Patricia, University of Utah, Murray, Utah, United States
  • Salant, David J., Boston University Medical Center, Boston, Massachusetts, United States
  • He, John C., Mount Sinai School of Medicine, New York, New York, United States
  • Mallipattu, Sandeep K., Stony Brook Medicine, Stony Brook, New York, United States

Pathologic glomerular epithelial cell (GEC) proliferation is characteristic of both RPGN and subtypes of FSGS. Although initial podocyte injury resulting in activation of signal transducer and activator of transcription (STAT) 3 signals GEC proliferation in both diseases, mechanism(s) regulating this process are largely unknown. Krüppel-Like Factor 4 (KLF4), a zinc finger transcription factor, is a negative regulator of proliferation and has recently been shown to inhibit STAT3 activation in neurons. Furthermore, KLF4 was previously shown to be renoprotective in proteinuric kidney disease. Based on these data, we hypothesize that podocyte-specific Klf4 deletion exacerbates pathologic GEC proliferation by activation of STAT3 signaling.


Podocyte-specific Klf4 knockout mice (Klf4ΔPod) were generated on C57BL/6 background by crossing Klf4fl/fl mice with Podocin-Cre mice. Nephrotoxic serum (NTS) nephritis was used to induce RPGN. Klf4ΔPod mice were backcrossed to a background susceptible to FSGS (FVB/n). Finally, human podocytes with stable knockdown of KLF4 (KLF4-shRNA) and overexpression of KLF4 (lentiORF-KLF4), with appropriate controls, were generated.


Glomerular KLF4 expression was increased 7 days after NTS treatment. NTS-treated Klf4ΔPod (C57BL/6) mice exhibited increased crescent formation, parietal epithelial cell (PEC) proliferation (Claudin1, Ki67), serum creatinine, and STAT3 signaling (phospho-STAT3, Il-6, Socs3 expression) as compared to NTS-treated wildtype mice. Untreated backcrossed Klf4ΔPod (FVB/n) mice exhibited STAT3 activation, cellular FSGS with PEC proliferation, renal failure, and a 50% increase in mortality as compared to wildtype mice at 12 weeks of age. Furthermore, basal STAT3 activation was significantly increased in wild-type FVB/n as compared to the C57BL/6 strain. Differentiated KLF4-shRNA podocytes also exhibited increased STAT3 activation with mitotic catastrophe (re-entry into cell cycle, actin destabilization) leading to reduced survival as compared with EV-shRNA podocytes. Conversely, these changes were rescued with re-induction of KLF4 (lentiORF-KLF4) in cultured podocytes.


Collectively these data suggest that KLF4 is a key regulator of STAT3-mediated aberrant GEC proliferation in RPGN and FSGS.


  • NIDDK Support