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Abstract: FR-PO981

Loss of Endothelial Klf4 Leads to Severe Glomerular Endothelial Injury in Aged Mice

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic


  • Estrada, Chelsea C., 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
  • Mallipattu, Sandeep K., Stony Brook Medicine, Stony Brook, New York, United States

Renal-specific thrombotic microangiopathy (TMA) represents the most severe form of renal microvascular injury, and is associated with activation of complement and dysregulation of key endothelial genes. To investigate transcriptional mediators involved in renal-TMA, we reviewed expression arrays of global and single cell RNA-seq from human kidney biopsies with complement mediated renal microvascular injury and observed that Krüppel-Like Factor 4 (KLF4), a zinc finger transcription factor, is both differentially expressed in endothelial cells (ECs) and predicted to regulate other differentially expressed genes. Although previous reports show that KLF4 coordinates an anti-thrombotic, anti-inflammatory phenotype in systemic vascular beds, its role in renal microvascular injury remains to be investigated.


Endothelial-specific Klf4 knockout mice (Klf4ΔEC) were generated by crossing Klf4fl/fl with Cdh5-Cre mice. Mice were aged to 1 year as a model of endothelial dysfunction. Periodic acid-Schiff, electron microscopy, immunofluorescence (IF), ELISA and RT-PCR were performed to investigate the effects of endothelial Klf4 in the renal microvasculature. Renal histology and ultrastructure were evaluated, blinded, by renal pathology (MPR).


We demonstrated 80% knockdown of endothelial KLF4 by RT-PCR and IF. At 12 weeks of age, while we did not observe any histologic changes, Klf4ΔEC mice exhibited increased glomerular Pai-1, Vcam-1 and decreased Nos3, as compared with Klf4fl/fl. Increased complement activation in glomerular capillaries was also noted in Klf4ΔEC mice (complement factor 3 and C5b-9 fragments by IF). In addition to an exacerbation of these findings, at 1 year, Klf4ΔEC mice exhibited histologic and ultrastructural changes observed across many TMA subtypes, including glomerular capillary dilation and congestion, EC swelling with loss of fenestrations, subendothelial expansion and mesangiolysis, as compared with aged matched controls. Furthermore, in line with this pathologic TMA signature, 1 year Klf4ΔEC mice also demonstrated increased glomerular von Willebrand factor and albuminuria, compared with age-matched controls.


Loss of endothelial Klf4 in aged mice recapitulates many pathologic features of renal-TMA, including complement activation and dysregulation of thrombotic and inflammatory genes.


  • NIDDK Support