RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

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.