Abstract: FR-PO334

Tubular-Specific Krüppel-Like Factor 15 Mediates the Progression from Tubular Injury to Interstitial Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis


  • Attallah, Ahmed A, Stony Brook Medicine, Stony Brook, New York, United States
  • Gu, Xiangchen, Yueyang hospital of integrated Traditional Chinese and Western Medicine, Shanghai, China
  • Guo, Yiqing, Stony Brook Medicine, Stony Brook, New York, United States
  • Mallipattu, Sandeep K., Stony Brook Medicine, Stony Brook, New York, United States

Mechanisms by which tubular injury results in fibroblast to myofibroblast differentiation in the transition from AKI to CKD remains poorly understood. Renal stromal-specific Krüppel-Like Factor 15 (KLF15), a zinc-finger transcription factor, was recently shown as a potential mediator of kidney fibrosis. Here, we sought to determine the mechanism by which the tubular KLF15 serves a key mediator of AKI to CKD in the setting of proximal tubular (PT) injury.


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 PT injury and AKI to CKD, 3 mg/kg every three days for 3 weeks, followed by 3 weeks for remodeling (DMSO served as control). Full-length ORF cDNA of human KLF15 (hKLF15) was cloned into a TRE plasmid. Mice with TRE-hKLF15 and Pax8-rtTA transgenes (Pax8-hKLF15) were generated for doxycycline (DOX) inducible tubule-specific hKLF15 induction. Finally, mice with TRE-hKLF15 and CAG-rtTA transgenes (CAG-hKLF15) were also generated for DOX-inducible global hKLF15 induction.


KLF15 mRNA and protein expression were reduced at 3 weeks post AAI treatment (AKI phase) and at 6 weeks (remodeling phase). Klf15ΔPepck mice exhibited an increase in pro-fibrotic markers (αSMA, Col1α1, fibronectin, vimentin) and myofibroblast proliferation (Ki67) as compared to AAI-treated wildtype mice. Klf15ΔPepck mice also demonstrated an increase in PT injury (AQP1 & lotus lectin redistribution and reduced expression) with activation of tubular Wnt/β-catenin signaling (nuclear phosho-β-catenin) and worsened renal function (elevated serum urea nitrogen and creatinine) compared to AAI-treated wildtype mice. Conversely, AAI-treated Pax8-hKLF15 mice exhibited a reduction in these pro-fibrotic markers, myofibroblast proliferation, and Wnt/β-catenin signaling with an improvement in PT markers as compared to AAI-treated wildtype mice. Finally, AAI-treated CAG-hKLF15 also validated this improvement in tubular injury, renal fibrosis, and renal function as compared to AAI-treated wildtype mice.


These data suggest that modulating the expression of tubular KLF15 is critical to the progression of AKI to CKD in the AAI-induced nephropathy, suggesting a potential target for therapy.


  • NIDDK Support