ArticleJournal of the American Society of Nephrology : JASN2018
The Calcium-Dependent Protease Calpain-1 Links TRPC6 Activity to Podocyte Injury.
Article in Journal of the American Society of Nephrology : JASN, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 73 citations in OpenAlex.
- Advances in SRNS Gene Research: From Precision Classification to Precision Diagnosis and Treatment.Biomedicines · 2026Review
- Bimodal regulation and precision therapy of neutrophil extracellular traps in liver ischemia-reperfusion injury: recent advances.Frontiers in immunology · 2026Review
- Talin1 modulates the Piezo1-YAP axis to regulate endothelial cell inflammation and atherosclerosis.Cellular and molecular life sciences : CMLS · 2025Article
- Single-atom Ca nanozyme induces glioma death through CaJournal of nanobiotechnology · 2025Article
- Research Progress on Anti-fibrotic Effects and Mechanisms of Tetrandrine.Chinese journal of integrative medicine · 2025Review
- The Life of a Kidney Podocyte.Acta physiologica (Oxford, England) · 2025Review
- TRPC6-targeted dexamethasone nanobubbles with ultrasound-guided theranostics for adriamycin-induced nephropathy.Journal of nanobiotechnology · 2025Article
- Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report.CEN case reports · 2025Article
- Advances in Focal Segmental Glomerulosclerosis Treatment From the Perspective of the Newest Mechanisms of Podocyte Injury.Drug design, development and therapy · 2025Review
- Article
- TRPC6 knockdown-mediated ERK1/2 inactivation alleviates podocyte injury in minimal change disease via upregulating Lon peptidase 1.Renal failure · 2024Article
- Genetically conditioned interaction among microRNA-155, alpha-klotho, and intra-renal RAS in male rats: Link to CKD progression.Physiological reports · 2024Article
- Associations of urinary fetuin-A with histopathology and kidney events in biopsy-proven kidney disease.Clinical kidney journal · 2024Article
- Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1.Signal transduction and targeted therapy · 2024Article
- The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing.Cell reports · 2023Article
- A Putative Role for TRPC6 in Immune-Mediated Kidney Injury.International journal of molecular sciences · 2023Review
- An inactivating human TRPC6 channel mutation without focal segmental glomerulosclerosis.Cellular and molecular life sciences : CMLS · 2023Article
- Store-operated CaExperimental biology and medicine (Maywood, N.J.) · 2023Review
- Ion channels and channelopathies in glomeruli.Physiological reviews · 2023Review
- The key role of Calpain in COVID-19 as a therapeutic strategy.Inflammopharmacology · 2022Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe hallmark of podocytopathies, such as FSGS, is podocyte injury resulting in proteinuria. Transient receptor potential channel C6 (TRPC6) is a calcium-conducting ion channel expressed at the slit diaphragm. TRPC6 gain-of-function mutations and glomerular TRPC6 overexpression are associated with proteinuria. However, the pathways linking TRPC6 to podocyte injury, which is characterized by loss of the slit diaphragm protein nephrin, activation of several intracellular pathways (including calcineurin-NFAT signaling), and cytoskeletal rearrangement, remain elusive.
methodsWe tested whether the calcium-dependent protease calpain-1 mediates TRPC6-dependent podocyte injury in human and experimental FSGS and cultured podocytes.
resultsCompared with kidneys of healthy controls, kidneys of patients with FSGS had increased TRPC6 expression, increased calpain and calcineurin activity, and reduced expression of the calpain target Talin-1, which links the actin cytoskeleton to integrins and is critical for podocyte cytoskeletal stability. In a rat model of human FSGS, increased glomerular and urinary calpain activity associated with reduced Talin-1 abundance, enhanced calcineurin activity, and increased proteinuria. Treatment with the calpain inhibitor calpeptin prevented these effects. In cultured podocytes, pharmacologic stimulation of TRPC6-dependent calcium influx increased calpain-1 and calcineurin activity and reduced Talin-1 expression, and knockdown of TRPC6 or calpain-1 prevented these effects.
conclusionsWe elucidated a novel mechanism that links TRPC6 activity to calpain-1 activation and through Talin-1 loss and possibly, calcineurin activation, the podocyte injury characterizing FSGS. Therefore, calpain-1 and/or TRPC6 inhibition could be future therapeutic options to treat patients with FSGS or other podocytopathies.
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