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Kidney Week

Abstract: FR-PO066

Loss of Proximal Tubular Krüppel-Like Factor 15 Exacerbates Renal Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Attallah, Ahmed A., Stony Brook University, Stony Brook, New York, United States
  • Gu, Xiangchen, Yueyang hospital of integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, SHANGHAI, China
  • Guo, Yiqing, Stony Brook University, Stony Brook, New York, United States
  • Piret, Sian, Stony Brook University, Stony Brook, New York, United States
  • Revelo Penafiel, Monica Patricia, University of Utah, Murray, Utah, United States
  • He, John Cijiang, Mount Sinai School of Medicine, New York, New York, United States
  • Mallipattu, Sandeep K., Stony Brook Medicine, Stony Brook, New York, United States

Although several causes contribute to the development of kidney fibrosis and eventual CKD, repeated bouts of acute tubular injury secondary to DNA damaging tubular toxins remains a major cause. Krüppel-Like Factor 15 (KLF15), a zinc-finger transcription factor that is expressed in renal stromal and proximal tubule (PT) cells was recently shown as a potential mediator of kidney fibrosis. KLF15 expression is reduced in early and late stages of human kidney fibrosis as compared to healthy control subjects. We sought to determine the mechanism by which tubular KLF15 serves a key mediator of DNA-damage induced PT injury leading to AKI and CKD.


PT-specific Klf15 knockout mice (Klf15ΔPepck) were generated by crossing Klf15fl/fl mice with Pepck-Cre mice. We utilized low-dose Aristolochic Acid I (AAI) to model DNA-damage induced PT injury, 3 mg/kg every three days for 2 weeks (active phase), followed by 2 weeks for remodeling (chronic phase), with DMSO as control. RNA-Seq was performed in active and remodeling phase samples.


Klf15ΔPepck mice demonstrated worse renal function (elevated serum urea nitrogen and creatinine), increased PT injury (AQP1 & lotus lectin redistribution and reduced expression) and changes in fibrotic markers compared to AAI-treated Klf15fl/fl mice in the acute and chronic phase. RNA-seq analysis showed that integrin signaling and focal adhesion pathways were upregulated in AAI-treated Klf15fl/fl mice. In the active phase a subset of 36 genes in metabolic & oxidative stress pathways were downregulated in Klf15ΔPepck but not in Klf15fl/fl and have KLF15 predicted binding sites (BS). In the chronic phase versus DMSO a subset of 13 genes including additional members of Focal adhesion, Regulation of actin cytoskeleton, integrin signaling and Inflammation pathways were upregulated in Klf15ΔPepck but not in Klf15fl/fl and have KLF15 BS. In the active to chronic transition a subset of 55 genes including additional members of Cell adhesion, Cell differentiation and Integrin signaling pathways were upregulated in Klf15ΔPepck but not in the Klf15fl/fl and have KLF15 BS.


These data suggest that the loss of tubular KLF15 exacerbates AAI-induced AKI and CKD, which is mediated by metabolic, focal adhesion and integrin signaling pathways.


  • NIDDK Support