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Kidney Week

Abstract: TH-PO538

Osteopontin Is a Key Orchestrator of Plasminogen Activator Inhibitor-1 (PAI-1) Induced Tubular Pathologies

Session Information

  • Pathology and Lab Medicine
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

  • 1700 Pathology and Lab Medicine

Authors

  • Gifford, Cody Charles, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Meyerson, Brian, Albany Medical Center, Albany, New York, United States
  • Goldschmeding, Roel, Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands
  • Samarakoon, Rohan, Albany Medical College Center for Cell Biology and Cancer Research, Albany, New York, United States
  • Higgins, Paul J., Albany Medical College Center for Cell Biology and Cancer Research, Albany, New York, United States
Background

Sustained tubular PAI-1 expression, evident in various renal diseases, promotes epithelial dedifferentiation, G2/M arrest and a prominent fibrotic response. It is unclear whether PAI-1-induced tubular maladaptive repair is linked to induction/secretion of pro-inflammatory/fibrotic molecules.

Methods

Employing cytokine protein array analysis as an un-biased approach, we identified novel factors upregulated in human kidney epithelial cells (HK2) stably overexpressing PAI-1 (termed CMV-PAI-1) compared to vector controls (termed CMV-Con). We identified specific cytokines pertinent to PAI-1-driven tubular pathologies via gene silencing approaches. Human fibrotic kidneys and obstructed rat kidneys were used to investigate the in vivo correlation between PAI-1 and associated cytokines via immunohistochemistry.

Results

Stable tubular PAI-1 expression resulted in induction and secretion of several cytokines/growth factors, including robust upregulation (15-fold) of osteopontin (OPN). Upregulation as well as co-localization of OPN and PAI-1 in the tubules of obstructed rat and human diabetic kidney sections (compared to respective control kidneys) suggested a potential relationship between PAI-1 and OPN during disease progression. shRNA-directed silencing of OPN in CMV-PAI-1 overexpressing HK2 renal tubular cells, indeed, attenuated PAI-1-mediated fibronectin, collagen-1 and p21 protein expression. Furthermore, OPN suppression in CMV-PAI-1 cells also reduced expression of the pro-fibrotic transcription factors, Twist, Snail1, p53 and phosphorylated-SMAD3. Twist gene depletion similarly ameliorated fibrotic maladaptive responses evident in CMV-PAI-1-transductants. Mechanistically, PAI-1-induced OPN upregulation requires downregulation of klotho and upregulation of TGF-β1-receptor signaling.

Conclusion

PAI-1 is a novel regulator of renal OPN induction observed during renal injuries. OPN is a key effector cytokine involved in PAI-1-induced tubular dysfunction and is an upstream control element of Twist and p53 transcription factors that drive fibrotic reprogramming. Targeting OPN induction in the kidney, therefore, is a new strategy to attenuate PAI-1-induced tubular dysfunction and CKD progression.

Funding

  • Other NIH Support