Discovery of endoplasmic reticulum calcium stabilizers to rescue ER-stressed podocytes in nephrotic syndrome

Sun Ji Park, Yeawon Kim, Shyh Ming Yang, Mark J. Henderson, Wei Yang, Maria Lindahl, Fumihiko Urano, Ying Maggie Chen

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Emerging evidence has established primary nephrotic syndrome (NS), including focal segmental glomerulosclerosis (FSGS), as a primary podocytopathy. Despite the underlying importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of NS, no treatment currently targets the podocyte ER. In our monogenic podocyte ER stress-induced NS/FSGS mouse model, the podocyte type 2 ryanodine receptor (RyR2)/calcium release channel on the ER was phosphorylated, resulting in ER calcium leak and cytosolic calcium elevation. The altered intracellular calcium homeostasis led to activation of calcium-dependent cytosolic protease calpain 2 and cleavage of its important downstream substrates, including the apoptotic molecule procaspase 12 and podocyte cytoskeletal protein talin 1. Importantly, a chemical compound, K201, can block RyR2-Ser2808 phosphorylation-mediated ER calcium depletion and podocyte injury in ER-stressed podocytes, as well as inhibit albuminuria in our NS model. In addition, we discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) can revert defective RyR2-induced ER calcium leak, a bioactivity for this ER stress-responsive protein. Thus, podocyte RyR2 remodeling contributes to ER stress-induced podocyte injury. K201 and MANF could be promising therapies for the treatment of podocyte ER stress-induced NS/FSGS.

Original languageEnglish
Pages (from-to)14154-14163
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number28
DOIs
StatePublished - 2019

Keywords

  • ER calcium stabilizer
  • Endoplasmic reticulum stress
  • K201
  • Podocytes
  • Type 2 ryanodine receptor

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