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Published on: August 4, 2022
mTOR-Dependent Autophagy Regulates Slit Diaphragm Density in Podocyte-like Drosophila Nephrocytes
Dominik Spitz1, Maria Comas1, Lea Gerstner1
1Renal Division, Department of Medicine, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany.
Abstract:
Both mTOR signaling and autophagy are important modulators of podocyte homeostasis, regeneration, and aging and have been implicated in glomerular diseases. However, the mechanistic role of these pathways for the glomerular filtration barrier remains poorly understood. We used Drosophila nephrocytes as an established podocyte model and found that inhibition of mTOR signaling resulted in increased spacing between slit diaphragms. Gain-of-function of mTOR signaling did not affect spacing, suggesting that additional cues limit the maximal slit diaphragm density. Interestingly, both activation and inhibition of mTOR signaling led to decreased nephrocyte function, indicating that a fine balance of signaling activity is needed for proper function. Furthermore, mTOR positively controlled cell size, survival, and the extent of the subcortical actin network. We also showed that basal autophagy in nephrocytes is required for survival and limits the expression of the sns (nephrin) but does not directly affect slit diaphragm formation or endocytic activity. However, using a genetic rescue approach, we demonstrated that excessive, mTOR-dependent autophagy is primarily responsible for slit diaphragm misspacing. In conclusion, we established this invertebrate podocyte model for mechanistic studies on the role of mTOR signaling and autophagy, and we discovered a direct mTOR/autophagy-dependent regulation of the slit diaphragm architecture.
Insights
mTOR signaling and autophagy regulate podocyte function and aging. Excessive mTOR-dependent autophagy causes slit diaphragm spacing defects, highlighting the need for balanced signaling in glomerular health.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Biology
Background:
- mTOR signaling and autophagy are crucial for podocyte homeostasis and implicated in kidney diseases.
- The precise roles of these pathways in the glomerular filtration barrier are not fully understood.
Purpose of the Study:
- To investigate the mechanistic roles of mTOR signaling and autophagy in podocyte function using a Drosophila model.
- To elucidate the regulation of slit diaphragm architecture by these pathways.
Main Methods:
- Utilized Drosophila nephrocytes as a model for podocytes.
- Employed genetic manipulation to inhibit or activate mTOR signaling.
- Assessed nephrocyte function, cell size, survival, actin network, and slit diaphragm spacing.
- Investigated the role of basal and excessive autophagy, including mTOR-dependent autophagy.
Main Results:
- Inhibition of mTOR signaling increased slit diaphragm spacing; gain-of-function did not affect spacing.
- Both mTOR activation and inhibition impaired nephrocyte function, indicating a need for balanced signaling.
- mTOR positively influenced cell size, survival, and actin network.
- Basal autophagy is essential for survival and limits nephrin expression.
- Excessive, mTOR-dependent autophagy was identified as the primary cause of slit diaphragm misspacing.
Conclusions:
- Drosophila nephrocytes serve as a valuable model for studying podocyte biology.
- mTOR signaling and autophagy are direct regulators of slit diaphragm architecture.
- A balanced regulation of mTOR and autophagy is critical for maintaining podocyte function and glomerular filtration barrier integrity.
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