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<p>Podocytopathies, driven by injury to glomerular podocytes, are a major cause of proteinuric kidney diseases like focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). The transient receptor potential canonical 6 (TRPC6) channel, expressed in podocytes, is critical for maintaining the glomerular filtration barrier. Dysregulation of TRPC6 activity-whether due to gain-of-function mutations or pathological activation-induces excessive calcium influx, leading to podocyte cytoskeletal disruption, oxidative stress, and apoptosis. While initially linked to hereditary FSGS, emerging evidence implicates TRPC6 dysfunction in diverse acquired podocytopathies, including DKD. This review explores the molecular mechanisms underlying TRPC6-mediated podocyte injury across these conditions, focusing on key calcium-dependent signaling pathways such as calcineurin/NFAT. It critically examines the role of TRPC6 as a therapeutic target, highlighting the rationale for its inhibition and the challenges involved in clinical translation. Understanding these mechanisms is crucial for developing strategies to prevent progression to end-stage renal disease.</p>

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Targeting TRPC6 in podocytopathies: Why clinical translation remains a challenge?

  • 期刊论文

  • 发表日期：

    2025年7月28日

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  • Chirag A. Patel,
  • Sudhirkumar Patel,
  • Sandip Patel,
  • Dharmishtha Parmar,
  • Jayesh Beladiya,
  • S. Rajesh Sundar,
  • Mukul Jain

摘要

Podocytopathies, driven by injury to glomerular podocytes, are a major cause of proteinuric kidney diseases like focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). The transient receptor potential canonical 6 (TRPC6) channel, expressed in podocytes, is critical for maintaining the glomerular filtration barrier. Dysregulation of TRPC6 activity-whether due to gain-of-function mutations or pathological activation-induces excessive calcium influx, leading to podocyte cytoskeletal disruption, oxidative stress, and apoptosis. While initially linked to hereditary FSGS, emerging evidence implicates TRPC6 dysfunction in diverse acquired podocytopathies, including DKD. This review explores the molecular mechanisms underlying TRPC6-mediated podocyte injury across these conditions, focusing on key calcium-dependent signaling pathways such as calcineurin/NFAT. It critically examines the role of TRPC6 as a therapeutic target, highlighting the rationale for its inhibition and the challenges involved in clinical translation. Understanding these mechanisms is crucial for developing strategies to prevent progression to end-stage renal disease.