ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: TH-PO409

Podocyte-Specific Partitioning Defective Par1a/b Deletion Increases Susceptibility to Adriamycin Nephropathy

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Mishra, Aparajita, Children's Hospital at Montefiore, New York, New York, United States
  • Du, Zhongfang, Albert Einstein College of Medicine, Bronx, New York, United States
  • Kurt, Selin, Montefiore Medical Center, Bronx, New York, United States
  • DiFranza, Lanny T., Montefiore Medical Center, Bronx, New York, United States
  • Brennan, Catherine Eileen, Albert Einstein College of Medicine, Bronx, New York, United States
  • Reidy, Kimberly J., Children's Hospital at Montefiore, New York, New York, United States
Background

The Partitioning-defective (Par1) proteins are serine threonine kinase members of a family of apico-basal polarity proteins that contribute to nephrocyte and podocyte differentiation and glomerular development in Drosophila and Mus musculus, respectively. However the role of Par1a/b following podocyte injury is not known. We hypothesized Par1a/b (aka Mark2 and Mark3) are protective against podocyte injury.

Methods

We examined correlation of glomerular Par1a/b (MARK2/3) gene expression with proteinuria using publicly available data from Nephroseq. Next, to test our hypothesis, we generated podocyte specific Par1a/b knockout (podocyte Par1a/b cKO): NPHS2-Cre: Mark2flox/flox: Mark3flox/flox which were maintained on a C57BL6 background. To determine the effect on podocyte injury, adult 8-week-old podocyte Par1a/b cKO mice were injected with adriamycin (15mg/kg). Controls included adriamycin injected Mark2flox/flox:Mark3flox/flox mice and vehicle injected mice. Mice were euthanized at 14 weeks to analyze the kidney phenotype. To analyze the severity of adriamycin nephropathy, Periodic-acid Schiff staining and urine albumin creatinine ratio were performed.

Results

Glomerular Par1a/MARK3 and Par1b/MARK2 expression was inversely correlated with proteinuria in multiple human gene expression data sets from subjects with glomerular disease (p<0.05). Podocyte Par1a/b cKO mice survive to adulthood, but more adriamycin treated Podocyte Par1a/b cKO died than Adriamycin treated flox/flox mice. Adriamycin treated Podocyte Par1a/b cKO mice had more global sclerosis and segmental sclerosis compared to the Adriamycin treated flox/flox controls (p<0.05). Adriamycin treated Podocyte Par1a/b cKO mice showed more albuminuria compared to the adriamycin flox/flox treated controls (p<0.05). Serum creatinine measurement showed no statistical difference among the groups.

Conclusion

Decreased Par1a/b (MARK2/3) expression correlates with more proteinuria in human glomerular disease. Podocyte Par1a/b deletion increased susceptibility to Adriamycin nephropathy, suggesting Par1a/b is protective following podocyte injury. Ongoing studies are examining the mechanism(s) by which podocyte Par1a/b deletion affects susceptibility to glomerular injury

Funding

  • NIDDK Support