Abstract: SA-PO204

The Protective Role of Podocyte Hypertrophy via mTOR Signalling after Mild Podocyte Depletion

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology

Authors

  • Puelles, Victor G., Monash University, Melbourne, Australia
  • Van der wolde, James W, Monash University, Melbourne, Victoria, Australia
  • Cullen-McEwen, Luise A., Monash University, Melbourne, Victoria, Australia
  • Furic, Luc, Monash University, Melbourne, Victoria, Australia
  • Denton, Kate M., Monash University, Melbourne, Victoria, Australia
  • Moeller, Marcus J., University Hospital RWTH Aachen, Aachen, Germany
  • Nikolic-Paterson, David J., Monash Medical Centre, Melbourne, Victoria, Australia
  • Bertram, John F., Monash University, Melbourne, Victoria, Australia
Background

Marked podocyte depletion is an established key feature of glomerulosclerosis (FSGS). However, little is known about the consequences of mild podocyte loss. In addition, activation of parietal epithelial cells (PECs) has been proposed as a major effector in FSGS. This study investigates the consequences of graded podocyte depletion, the hypertrophic response of podocytes and associations with PEC activation and thereby glomerulosclerosis.

Methods

We induced selective podocyte depletion in PodCreiDTR mice by injection of diphtheria toxin (DT) at different doses. L-NAME induced hypertension was used as a second hit challenge after mild podocyte loss. The mammalian target of rapamycin (mTOR) signalling pathway was manipulated using mTOR inhibitors (RAD001 and INK128). Podocyte depletion and hypertrophy were examined by 3D analysis of whole glomeruli in optically-cleared kidney slices.

Results

PodCreiDTR mice injected with a low dose of DT presented mild podocyte depletion, compensatory podocyte hypertrophy and reversible albuminuria without PEC activation or glomerulosclerosis, even following a second hit challenge (high blood pressure), suggesting a protective role of podocyte hypertrophy. Injection of a higher dose of DT in PodCreiDTR mice led to greater podocyte loss and hypertrophy. However, these mice showed PEC activation, glomerulosclerosis and persistent albuminuria, suggesting there is a limit for the protective role of podocyte hypertrophy. Pharmacological inhibition of mTOR during the induction of mild podocyte depletion led to persistent and exacerbated albuminuria, impairment of podocyte hypertrophy, PEC activation and glomerulosclerosis.

Conclusion

Podocyte hypertrophy via mTOR signalling is required for the adaptive hypertrophic response of remaining podocytes after mild podocyte depletion. These results are relevant for the use of mTOR inhibitors in the context of FSGS and CKD.