Abstract: FR-OR112

Pik3c3-Dependent mTORC1 Signaling Mediates Compensatory Nephron Hypertrophy

Session Information

Category: Cell Biology

  • 201 Cell Signaling, Oxidative Stress

Authors

  • Liu, Ting, Augusta University, Augusta, Georgia, United States
  • Xu, Jinxian, Augusta University, Augusta, Georgia, United States
  • Humphreys, Benjamin D., Washington University School of Medicine, Clayton, Missouri, United States
  • Dai, Caihong, Augusta University, Augusta, Georgia, United States
  • Chen, Jian-Kang, Augusta University, Augusta, Georgia, United States
Background

Nephron loss stimulates the residual nephrons to undergo compensatory nephron hypertrophy (CNH), which is implicated in progressive nephron damage. Activation of the mechanistic (formerly mammalian) target of rapamycin complex 1 (mTORC1) mediates uninephrectomy (UNX)-induced CNH. We recently observed class 3 phosphatidylinositol 3-kinase (Pik3c3) activation in the remaining kidney after UNX. However, whether Pik3c3 activation is essential for mTORC1 activation and CNH remains undefined.

Methods

We created homozygous Pik3c3-hypomorphic (Hypo) mice to compare with gender-matched heterozygous (Het) and wild type (WT) littermates. We also created tamoxifen-inducible proximal tubule-specific Pik3c3 knockout (KO) mice, which have a genotype of Pik3c3flox/flox;SLC34a1.CreERT2(+). Gender-matched Pik3c3flox/flox;CreERT2(-) littermates were used as controls (Ctrl) mice.

Results

Hypo mice express markedly less Pik3c3 than Het littermates, which already express a lower level of Pik3c3 than WT littermates. Interestingly, when subjected to UNX, Hypo mice developed less CNH than both WT and Het mice, revealed by UNX-induced increases in kidney-to-body weight ratio (WT: 31.78±1.89 vs. Hypo: 18.10±1.31%, p<0.0001; Het: 27.14±1.04 vs. Hypo: 18.10±1.31%, p<0.001; n=5-7). Consistently, UNX induced significantly less CNH in KO mice than in Ctrl mice, indicated by UNX-induced increases in kidney-to-body weight ratio (Ctrl: 33.15±1.97 vs. KO: 15.81±2.82%, p<0.001; n=7) as well as protein-to-DNA ratio (Ctrl: 25.00±4.01 vs. KO: 9.78±2.88%, p<0.05; n=7). Signaling studies with immunoblotting and immunostaining unveiled that UNX-induced mTORC1 activation in the remaining kidney was markedly inhibited in both Pik3c3-hypomorphic and Pik3c3-KO models.

Conclusion

The present study using two genetically engineered mouse models provides unequivocal evidence that Pik3c3-dependent mTORC1 activation is a major mechanism underlying nephron loss-induced residual nephron hypertrophy.

Funding

  • NIDDK Support