ArticleJCI insight2020
Inhibiting calpain 1 and 2 in cyclin G associated kinase-knockout mice mitigates podocyte injury.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- Approach to Studies on Podocyte Lesions Mediated by Hyperglycemia: A Systematic Review.International journal of molecular sciences · 2025Pooled it
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- Identification and validation of biomarkers in membranous nephropathy and pan-cancer analysis.Frontiers in immunology · 2024Article
- Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases.The Journal of clinical investigation · 2023Article
- Recent progress in discovery of novel AAK1 inhibitors: from pain therapy to potential anti-viral agents.Journal of enzyme inhibition and medicinal chemistry · 2023Review
- VPA improves ferroptosis in tubular epithelial cells after cisplatin-induced acute kidney injury.Frontiers in pharmacology · 2023Article
- Efficacy of leupeptin in treating ischemia in a rat hind limb model.Physiological reports · 2022Article
- Enhanced Orai1-mediated store-operated CaThe Journal of biological chemistry · 2022Article
- Visualizing Cell Death in Live Retina: Using Calpain Activity Detection as a Biomarker for Retinal Degeneration.International journal of molecular sciences · 2022Article
- Podocyte Endocytosis in Regulating the Glomerular Filtration Barrier.Frontiers in medicine · 2022Review
- Calpain Inhibitor Calpeptin Alleviates Ischemia/Reperfusion-Induced Acute Kidney InjuryFrontiers in medicine · 2022Article
- Cytoskeleton Rearrangements Modulate TRPC6 Channel Activity in Podocytes.International journal of molecular sciences · 2021Article
- Gak loss promotes calpain-induced injury.Nature reviews. Nephrology · 2021Article
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Authors and funding
18 authors at 6 institutions in 3 countries.
Funding
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-KO mice. Our results suggest that loss of podocyte-associated Gak induces glomerular injury secondary to calcium dysregulation and aberrant calpain activation, which when inhibited, can provide a protective role.
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