RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death.

So-Young Kim,Eun Young Lee,Eun Soo Lee,Samel Park,Miri Kim,Youngjo Kim,Jong-Seok Moon,Choon Hee Chung,Ji-Hye Lee,Seong-Woo Lee,Jeong Suk Kang

doi:10.3390/cells10020245

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.

Highlights

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-galA) [1,2]
Studies on the association between Receptorinteracting protein kinase 3 (RIPK3) and chronic kidney disease (CKD) are lacking, we reported that RIPK3 played an important role in kidney fibrosis via the AKT
We treated podocytes with lyso-Gb3 in vitro to investigate whether lyso-Gb3 treatment resulted in podocyte death, representing the Fabry nephropathy model

Summary

Introduction

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-galA) [1,2]. 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 Deficient or decreased activity of the enzyme leads to the progressive intracellular or lysosomal accumulation of globotriaosylceramide (Gb3) [3]. Fabry disease has serious clinical manifestations, including stroke, cardiomyopathy, renal failure, and death [4], the diagnosis of Fabry disease is challenging, especially in the early period of the disease [5]. The leading cause of death in patients with Fabry disease is cardiovascular disease, renal failure was the most common clinical event in male patients who died of cardiovascular disease [6]. Male patients with Fabry nephropathy reach end-stage kidney disease (ESKD) in the third to fifth decade of life [8]

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