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RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death
So-Young Kim1, Samel Park1,2, Seong-Woo Lee1,3
1Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Korea.
Abstract:
Fabry disease is a lysosomal storage disease with an X-linked heritage caused by absent or decreased activity of lysosomal enzymes named alpha-galactosidase A (α-gal A). Among the various manifestations of Fabry disease, Fabry nephropathy significantly affects patients' morbidity and mortality. The cellular mechanisms of kidney damage have not been elusively described. Necroptosis is one of the programmed necrotic cell death pathways and is known to play many important roles in kidney injury. We investigated whether RIPK3, a protein phosphokinase with an important role in necroptosis, played a crucial role in the pathogenesis of Fabry nephropathy both in vitro and in vivo. The cell viability of podocytes decreased after lyso-Gb3 treatment in a dose-dependent manner, with increasing RIPK3 expression. Increased reactive oxygen species (ROS) generation after lyso-Gb3 treatment, which was alleviated by GSK'872 (a RIPK3 inhibitor), suggested a role of oxidative stress via a RIPK3-dependent pathway. Cytoskeleton rearrangement induced by lyso-Gb3 was normalized by the RIPK3 inhibitor. When mice were injected with lyso-Gb3, increased urine albuminuria, decreased podocyte counts in the glomeruli, and effaced foot processes were observed. Our results showed that lyso-Gb3 initiated albuminuria, a clinical manifestation of Fabry nephropathy, by podocyte loss and subsequent foot process effacement. These findings suggest a novel pathway in Fabry nephropathy.
Insights
Fabry disease kidney damage involves cell death pathways. Research shows RIPK3 protein kinase mediates podocyte injury and albuminuria in Fabry nephropathy via oxidative stress.
Area of Science:
- Nephrology
- Cell Biology
- Genetics
Background:
- Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency.
- Fabry nephropathy is a major cause of morbidity and mortality, with unclear cellular mechanisms of kidney damage.
- Necroptosis, a programmed cell death pathway involving RIPK3, is implicated in kidney injury.
Purpose of the Study:
- To investigate the role of RIPK3 in the pathogenesis of Fabry nephropathy.
- To explore the mechanisms of kidney damage induced by lyso-Gb3, the accumulating substrate in Fabry disease.
Main Methods:
- In vitro studies using podocytes treated with lyso-Gb3 and a RIPK3 inhibitor (GSK'872).
- In vivo studies involving mice injected with lyso-Gb3.
- Assessment of cell viability, reactive oxygen species (ROS) generation, cytoskeleton rearrangement, albuminuria, and podocyte morphology.
Main Results:
- Lyso-Gb3 decreased podocyte viability and increased RIPK3 expression and ROS generation in a dose-dependent manner.
- RIPK3 inhibition alleviated oxidative stress and normalized cytoskeleton rearrangement induced by lyso-Gb3.
- In vivo, lyso-Gb3 induced albuminuria, podocyte loss, and foot process effacement, indicating RIPK3-dependent podocyte injury.
Conclusions:
- RIPK3 plays a crucial role in Fabry nephropathy pathogenesis.
- Lyso-Gb3 induces kidney damage through a RIPK3-dependent pathway involving oxidative stress and podocyte injury.
- This study suggests a novel therapeutic target for Fabry nephropathy.
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