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Kidney Week

Abstract: SA-PO078

PTIP Deletion in Renal Proximal Tubules May Cause Epigenetic Change and Prevent Recovery After AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Soofi, Abdul A., University of Michigan, Ann Arbor, Michigan, United States
  • Dressler, Greg R., University of Michigan, Ann Arbor, Michigan, United States
Background

Paxip1gene encodes a PTIP nuclear protein that is expressed in most cells and is implicated in a variety of nuclear processes, including DNA repair, and transcription activation. Consequent to acute kidney injury (AKI), surviving proximal tubule cells re-enter mitosis and will form cysts if disease associated genes are mutated. Thus, epigenetic information that maintain a stable phenotype must be reset during regeneration. PTIP is part of an Mll3/4 histone H3K4 methyltransferase complex that is essential for development. To test whether such epigenetic imprints are dependent on histone H3K4 methylation, we generated a mouse model with deletion of PTIP (PTIP-) in the terminally differentiated renal proximal tubular cells.

Methods

We used Cre-loxP system, standard genetic and biochemical techniques to generate and study the deletion of PTIP- specifically in renal proximal tubular cells. Also mice carried the mT/mG; Pepck-cre. Mice were age-matched and injected i.p with a single dose of folic acid.

Results

The kidneys of mice carrying the PTIP- appeared normal with little evidence of loss of kidney function or other abnormalities. Upon AKI, such mice failed to regenerate damaged tubules leading to scarring and interstitial fibrosis. The inability to repair damage was likely due to a failure to re-enter mitosis and reactivate regulatory genes such as Sox9. PTIP- reduced histone H3K4M3 in uninjured kidneys but had no effect on H3K4M2. A transient decrease in trimethylation was also observed in controls after AKI but returned to normal after repair. Strikingly, cell lineage tracing revealed that surviving PTIP mutant cells could alter their phenotype and lose epithelial markers. These data demonstrate that PTIP is needed for regenerating proximal tubules and to maintain or reestablish the cellular phenotype

Conclusion

The process of regeneration must require changes in gene expression of surviving epithelial cells, which may involve the reactivation of genes controlling development and proliferation. Despite PTIP-, mice had no gross morphological phenotypes, suggesting that PTIP- at this stage of differentiation had little apparent effect on kidney function. However, when such mice were subjected to AKI, the ability to repair and repopulate damaged tubules was severely compromised.

Funding

  • Other NIH Support