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Abstract: FR-PO102

Partitioning Defective Par1a Deletion Attenuates Renal Fibrosis in Mice

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Maria, Estefany, Albert Einstein College of Medicine, Bronx, New York, United States
  • Pal, Abhijeet, The Children's Hospital at OU Medical Center, Oklahoma City, Oklahoma, United States
  • Du, Zhongfang, Albert Einstein College of Medicine, Children''s Hospital at Montefiore, Bronx, New York, United States
  • Reidy, Kimberly J., Children's Hospital at Montefiore/ Albert Einstein College of Medicine, Bronx, New York, United States
Background

Chronic kidney disease (CKD) affects 1 in 7 U.S. adults; CKD leads to both increased morbidity and mortality. CKD progression correlates with tubulointerstitial fibrosis. As shown in mouse models, fibrosis is driven by Notch and Wnt activation. Notch and Wnt are important renal developmental pathways. In prior work from our laboratory focused on the developing kidney, Notch signaling pathway expression was decreased in Par1a/b mutant mice (Par1a+/-:Par1b-/-). Par1a and 1b are serine threonine kinases: they regulate protein trafficking, cell-cell adhesion, cell-matrix adhesion and the actin cytoskeleton. Par1a and 1b are paralogues and compensate for one another: while Par1a+/-:Par1b-/- mice die after birth, individual Par1a or 1b knockout mice have no renal developmental phenotype. We hypothesized: Loss of Par1a or 1b would attenuate Notch signaling and renal fibrosis.

Methods

To examine the expression of Par1a/b and Notch signaling components in renal injury, immunoflorescence (IF) staining was performed; Par1a and 1b paralogue specific antibodies were used. For acute kidney injury, mice were injected with 20 mg/kg cisplatin injection i.p. For chronic kidney injury, folic acid nephropathy and unilateral ureteral obstruction were used. To test the role of Par1a in renal fibrosis, folic acid injection (250 mg/kg dissolved in 300 mM NaHCO3) was performed in Par1a-/- and Par1a+/+ mice. Vehicle injected mice served as controls. To detect renal fibrosis, Picrosirius red staining of collagen was performed. Quantification of 20x images was performed using Image J.

Results

Par1b expression increased in acute kidney injury, while Par1a expression increased predominantly in chronic kidney injury models.
Consistent with other studies, Notch signaling component expression also increased following kidney injury. Folic acid injected Par1a-/- mice had decreased renal fibrosis: as quantified by sirius red staining, percent area of fibrosis was 12 +/- 6.8 % in folic acid treated Par1a+/+ vs 3 +/- 2.2% in Par1a-/- kidneys. (p-value <0.01)

Conclusion

Par1a and Notch signaling pathway member expression are increased in renal fibrosis mouse models. In mice, Par1a deletion was protective against fibrosis. Par1a is a potential modifier of Notch activation during renal fibrosis.

Funding

  • NIDDK Support