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Abstract: SA-PO339

Partitioning-Defective (Par1) Inhibition Protects Against Kidney Fibrosis in Mice

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Reidy, Kimberly J., Albert Einstein College of Medicine, Bronx, New York, United States
  • Du, Zhongfang, Albert Einstein College of Medicine, Bronx, New York, United States
  • Zhou, Vellia, Albert Einstein College of Medicine, Bronx, New York, United States
Background

Partioning defective (Par) 1a and 1b (MARK2/3) expression is required for normal kidney development and increases in damaged tubules following tubular injury by unilateral ureteral obstruction (UUO) and folic acid (FA) injection in mice. Par1a/MARK3 expression in human kidney tissues correlates with kidney fibrosis and eGFR. Par1a mutant (Mark3-/-) mice are protected against kidney fibrosis following UUO and FA induced injury. We hypothesized tubular Par1a/b expression is maladaptive following kidney injury and sought to test the effect of tubular Par1a/b deletion and chemical Par1 inhibition on fibrosis following kidney injury.

Methods

We generated tubular conditional Par1a/b knock out mice (Pax8-rtTA:tet-O-Cre:Mark2flox/flox:Mark3flox/flox) mice. Tubular deletion was induced using doxycycline treatment 7 days prior to injury by UUO. Sham operated (for UUO) mice was used as control for the injury model. Both injured and uninjured uninduced Pax8-rtTA:tet-O-Cre:Mark2flox/flox:Mark3flox/flox mice and doxycyline treated Mark2flox/flox:Mark3flox/flox mice were used as controls. A MARK/Par-1 Activity Inhibitor (Sigma, 39621) was injected via IP injection for 3 days after UUO injury. Kidney phenotype was analyzed at 7 days post UUO injury or sham surgery.

Results

Par1a/b (Mark2/3) gene expression is highest in injured, dedifferentiated proliferating (Sox9 and Ki67+) tubular cells. Dual Par1a/b cKO mice were protected from injury induced fibrosis following UUO induced injury (p=0.001). MARK Inhibition after injury protected against UUO induced fibrosis.

Conclusion

Genetic tubular deletion of Par1a/b before injury and inhibition post UUO induced injury was protective against kidney fibrosis. Ongoing experiments are testing other models of kidney injury and mechanisms of Par1a/b protection.

Funding

  • NIDDK Support