PLCε regulates podocyte differentiation and TGF-β1 responses via alteration of SMAD2/SMAD3 ratio.

BACKGROUND

Amongst genetic causes of nephrotic syndrome (NS), mutations in the PLCΕ1 gene have been described in patients with early onset NS and diffuse mesangial sclerosis (DMS). However, little is known about how these mutations alter podocyte biology although a role in podocyte differentiation has been proposed (Yu S, et al. Exp Mol Med. 52(4):594-603,2020).

METHODS

To explore the role of PLCε in podocytes, A conditionally immortalised human podocyte cell line was generated from a patient with early onset NS, due to a nonsense PLCΕ1 mutation, resulting histologically in diffuse mesangial sclerosis (DMS).

RESULTS

In comparison to wild type podocytes, the PLCΕ1 mutant podocyte cell has reduced epithelial features, altered actin cytoskeleton and significantly lower levels of the epithelial marker ZO-1.

CONCLUSIONS

We demonstrate that PLCε deficiency is associated with functionally impaired TGF-β1 responses with an altered SMAD2/SMAD3 ratio and absent SMAD2 phosphorylation, resulting in loss of the motility response to TGF-β1. We further show that PLCE1 knockdown in wild-type podocytes recapitulates this phenotype by knock-down of PLCΕ1 in wild-type podocytes. This work reveals that disease-causing mutations in PLCΕ1 result in podocyte dedifferentiation and uncovers a novel association between PLCΕ1 deficiency and SMAD2/3 signalling signalling in maintaining podocyte differentiation.