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Kidney Week

Abstract: SA-PO1003

Tubule-Specific Overexpression of Krüppel-Like Factor 6 (KLF6) Is Detrimental After Nephrotoxic Kidney Injury

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms


  • Piret, Sian, Stony Brook University, Stony Brook, New York, United States
  • Davis, Merin, Stony Brook University, Stony Brook, New York, United States
  • Gholami, Samaneh, Stony Brook University, Stony Brook, New York, United States
  • Gujarati, Nehaben A., Stony Brook University, Stony Brook, New York, United States
  • Owusu Frimpong, Bismark, Stony Brook University, Stony Brook, New York, United States
  • Mallipattu, Sandeep K., Stony Brook University, Stony Brook, New York, United States

Transcriptional control of transition to chronic kidney disease (CKD) after nephrotoxic injury is poorly understood. We previously showed that proximal tubule (PT)-specific knockdown of the transcription factor Krüppel-like factor 6 (KLF6) was protective after DNA damage using the PT-specific toxin aristolochic acid I (AAI). Our aim was to determine whether tubular overexpression (OE) of human (h)KLF6 (hKLF6TOE) attenuates remodeling of the kidney post-AAI.


hKLF6TOE mice were generated by breeding TRE-hKLF6 and Pax8-rtTA mice, with doxycycline (DOX) added to the diet. Controls were single transgenic TRE-hKLF6 mice. AAI was injected at 2mg/kg every 3 days for 2 weeks, followed by 2 weeks without AAI for development of CKD. Serum was collected for urea nitrogen and creatinine measurements, and kidneys for histology and gene expression analyses. Single nuclear RNA-sequencing (snRNA-seq) was undertaken on global hKLF6-OE mice 24 hours after one AAI injection. Locations of p53 and KLF6 binding sites (BS) from published ChIP-seq data were mapped against regions of open chromatin in published data from mouse nephron.


To determine whether hKLF6 OE alone would induce injury, hKLF6TOE and control mice were fed DOX for 18 weeks. There were no functional or histological differences between hKLF6TOE and control mice at baseline. AAI-treated hKLF6TOE mice had elevated serum creatinine and urea nitrogen, and more PT injury, inflammation, and fibrosis as compared to AAI-treated controls. To determine potential mechanisms, we utilized snRNA-seq in global hKLF6-OE mice. The most highly upregulated pathway both in PT from control mice with AAI versus no AAI, and in an injured-PT cluster, was p53 signaling, which was further elevated in hKLF6-OE mice. In silico ChIP-seq showed p53 and KLF6 occupy the promoters of key p53 downstream targets. In hKLF6TOE mice cortex, expression of two p53 pathway members, Ccng1 (which has KLF6 BS) and Mdm2 (p53 and KLF6 BS), was significantly correlated with hKLF6 expression. Total KLF6 expression also correlated with serum creatinine and urea nitrogen levels in AAI-treated control and hKLF6TOE mice.


Induction of tubule-specific KLF6 exacerbates the AKI to CKD transition post-nephrotoxic injury, which may be mediated through enhanced p53 signaling.