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An Inducible hiPSC-Derived Human Podocyte Model for Functional Analysis of TRPC6 Variants Associated with FSGS
Lilas Batool1, Krithika Hariharan2, Gabriel Stölting3
1Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Cells
|April 27, 2026
Summary
Focal segmental glomerulosclerosis (FSGS) involves podocyte injury and altered calcium levels. This study developed a human induced pluripotent stem cell (hiPSC) model to investigate TRPC6 mutations in FSGS, revealing insights into disease mechanisms.
Area of Science:
- Nephrology
- Stem Cell Biology
- Molecular Genetics
Background:
- Podocyte injury is central to focal segmental glomerulosclerosis (FSGS), leading to nephrosis, proteinuria, and glomerulosclerosis.
- Intracellular calcium homeostasis in podocytes is crucial; dysregulation causes foot process effacement, apoptosis, and nephron degeneration.
- The canonical transient receptor potential 6 (TRPC6) channel regulates podocyte calcium flux, and its mutations are linked to FSGS.
Purpose of the Study:
- To develop and characterize an inducible human induced pluripotent stem cell (hiPSC) model for studying FSGS.
- To investigate the impact of TRPC6 gain-of-function (GoF) and loss-of-function (LoF) mutations on calcium influx in differentiated podocytes.
- To establish a platform for in vitro disease mechanism studies and therapeutic intervention screening for FSGS.
Main Methods:
- Generation and phenotypic characterization of three transgenic hiPSC lines with inducible TRPC6 overexpression (wild-type, GoF mutant P112Q, LoF mutant G757D).
- Differentiation of hiPSC lines into induced podocytes (ipodocytes).
- Assessment of calcium influx in ipodocytes using TRPC6 agonists and antagonists to evaluate mutant phenotypes.
Main Results:
- Successful generation of hiPSC lines with regulatable TRPC6 expression, including FSGS-associated mutants.
- Differentiated ipodocytes exhibited calcium responses consistent with the predicted GoF and LoF phenotypes of TRPC6 mutations.
- The developed model system effectively demonstrated the impact of TRPC6 mutations on calcium homeostasis in podocytes.
Conclusions:
- The developed inducible hiPSC-based model provides a robust system for studying FSGS in vitro.
- This model allows for detailed investigation of TRPC6 mutation effects on podocyte calcium signaling.
- The platform is valuable for advancing understanding of FSGS pathogenesis and exploring potential therapeutic strategies.
