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Kidney Week

Abstract: FR-PO349

Par1a Deletion Protects Against Folic Acid and Unilateral Ureteral Obstruction-Induced Fibrosis in Mice

Session Information

  • CKD: Mechanisms - II
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms


  • Zhou, Vellia, Albert Einstein College of Medicine, Bayside, New York, United States
  • Du, Zhongfang, Albert Einstein College of Medicine, Bayside, New York, United States
  • Reidy, Kimberly J., Children's Hospital at Montefiore/ Albert Einstein College of Medicine, Bronxville, New York, United States

We recently identifed Par1 serine threonine kinases as regulators of Notch signaling in the developing kidney: dual loss of Par1a/b led to impaired Notch activation and glomerular and proximal tubular development. Par1a expression increases following unilateral ureteral obstruction (UUO) and folic acid (FA) induced injury. However, the effect of Par1a deletion on renal fibrosis is not known. We hypothesized: Loss of Par1a would attenuate Notch signaling activation and renal fibrosis.


Immunoflorescence staining was used to examine the expression of Par1a/b and Notch signaling components. To test effect of Par1a deletion on fibrosis in vivo, FA (250 mg/kg dissolved in 300 mM NaHCO3) or vehicle was injected in 5 week old male Par1a -/- (Par1a KO) and Par1a +/+ (Par1a) WT littermates. Kidney phenotype was assessed at 4 weeks post injection. UUO was performed in adult (10 week old) male Par1a KO and WT littermates; phenotype was examined at 7 days. 6-8 mice/group were studied. To detect renal fibrosis, Picrosirius red staining of collagen was performed. Polarized light and Image J was utilized to quantify fibrosis on 200 x images. Primary tubular cell cultures were generated from inducible Par1 knockout (Pax8rtTA:tetOCre: Par1flox/flox) mice. Cultures were exposed to TGFbeta (10 ng/mL) and examined at 72 hours. Doxycycline was used to induce Par1 deletion.


Both Par1a and Jag1 expression increase following FA and UUO injury in mice. Par1a and Jag1 co-localized in kidney tubules following FA and UUO induced injury. Par1a deletion was protective against renal fibrosis in mice: as quantified by sirius red staining, % area of fibrosis was 1.4 ± 0.9 vs. 0.8 ± 0.5 in FA treated Par1a WT vs. KO kidneys. Following UUO, % area fibrosis was 2.75 ± 2.3 vs. 0.76 ± 0.29 in Par1a WT vs. KO kidneys.(p<0.01) Par1 deletion was protective against TGFbeta induced renal tubular damage in vitro. Whereas E-cadherin expression was lost with TGFbeta treatment in control primary tubular cells, Par1 knockout cells had preserved E-cadherin expression following TGFbeta exposure.


Par1a deletion is protective against renal fibrosis in mice. Par1 deletion was protective against renal tubular injury in vitro, suggesting tubular Par1 mediates its protecitve effects. Colocalization of Par1 and Jag1 suggests Par1 may affect Jag1 mediated Notch activation.


  • NIDDK Support