Why the study?
Pathogenic variants in TRPC6 can cause FSGS through dysregulated calcium conductance, but specific novel mutations and their mechanistic effects require characterization.
Does sildenafil and losartan combination therapy improve podocyte barrier function and reduce protein aggresomes in patient-specific iPSC-derived podocytes with a novel TRPC6 mutation?
Does sildenafil and losartan combination therapy improve podocyte barrier function and reduce protein aggresomes in patient-specific iPSC-derived podocytes with a novel TRPC6 mutation?
Sildenafil and losartan combination therapy ameliorates podocyte injury and barrier dysfunction in a novel TRPC6 mutation-associated FSGS model, outperforming conventional calcineurin inhibitor therapy.
Hypothesis-generating in TRPC6-mutant FSGS models; leaves open whether sildenafil-losartan improves clinical outcomes.
SUMMARY FSGS is the most common primary glomerular lesion that causes kidney failure in the US. FSGS results from injury or loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic variants in TRPC6 can cause FSGS through dysregulated calcium conductance and associated disturbances in podocyte physiology. Here, we describe a 5-generation kindred with FSGS caused by a novel compound C-terminal TRPC6 mutation. Analysis of patient-specific iPSC-derived podocytes and glomerular capillary wall-on-a-chip systems revealed that the compound variants disrupt TRPC6 protein structure, intermolecular interactions, and membrane localization. Combined therapy with Sildenafil and Losartan ameliorated these disturbances compared to conventional immunosuppressive treatment.
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Bhattacharya et al. (2025) studied this question.
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