Inhibiting calpain 1 and 2 in cyclin G associated kinase-knockout mice mitigates podocyte injury.

JCI Insight
Xuefei TianShuta Ishibe

Abstract

Evidence for reduced expression of cyclin G associated kinase (GAK) in glomeruli of patients with chronic kidney disease was observed in the Nephroseq human database, and GAK was found to be associated with the decline in kidney function. To examine the role of GAK, a protein that functions to uncoat clathrin during endocytosis, we generated podocyte-specific Gak-knockout mice (Gak-KO), which developed progressive proteinuria and kidney failure with global glomerulosclerosis. We isolated glomeruli from the mice carrying the mutation to perform messenger RNA profiling and unearthed evidence for dysregulated podocyte calpain protease activity as an important contributor to progressive podocyte damage. Treatment with calpain inhibitor III specifically inhibited calpain-1/-2 activities, mitigated the degree of proteinuria and glomerulosclerosis, and led to a striking increase in survival in the Gak-KO mice. Podocyte-specific deletion of Capns1, essential for calpain-1 and calpain-2 activities, also improved proteinuria and glomerulosclerosis in Gak-KO mice. Increased podocyte calpain activity-mediated proteolysis of IκBα resulted in increased NF-κB p65-induced expression of growth arrest and DNA-damage-inducible 45 beta in the Gak-...Continue Reading

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Citations

Dec 6, 2020·Nature Reviews. Nephrology·Monica Wang
May 1, 2021·International Journal of Molecular Sciences·Alexey ShalyginElena Kaznacheyeva
May 2, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yuzhan ZhangRongguo Fu

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Datasets Mentioned

BETA
GSE158384

Methods Mentioned

BETA
transgenic
biopsies
genotyping
transmission electron microscopy
PCR
immunoprecipitation
affinity purification
ChIP
ELISA
density gradient centrifugation

Software Mentioned

IPA
GraphPad Prism
R Bioconductor package
NIH ImageJ
Nephroseq
Adobe Photoshop

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