Abstract: TH-PO409
Podocyte-Specific Partitioning Defective Par1a/b Deletion Increases Susceptibility to Adriamycin Nephropathy
Session Information
- Development, Organoids, Injury, and Regeneration
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
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