Abstract
PLCE1 encodes phospholipase C epsilon, and its mutations cause recessive nephrotic syndrome. However, the mechanisms by which PLCE1 mutations result in defects associated with glomerular function are not clear. To address this, we investigated the function of PLCE1 in podocytes called glomerular epithelial cells, where the pathogenesis of nephrotic syndrome converges. PLCE1 colocalized with Rho GTPases in glomeruli. Further, it interacted with Rho GTPases through the pleckstrin homology domain and Ras GTP-binding domains 1/2. Knockdown or knockout of PLCE1 in podocytes resulted in decreased levels of GTP-bound Rac1 and Cdc42, but not those of RhoA, and caused a reduction in cell migration. PLCE1 interacted with NCK2 but not with NCK1. Similar to the PLCE1 knockout, NCK2 knockout resulted in decreased podocyte migration. Knockout of PLCE1 reduced the EGF-induced activation of ERK and cell proliferation in podocytes, whereas knockout of NCK2 did not affect proliferation. Further, the knockout of PLCE1 also resulted in decreased expression of podocyte markers, including NEPH1, NPHS1, WT1, and SYNPO, upon differentiation, but the knockout of NCK2 did not affect the expression of these markers. Therefore, our findings demonstrate that PLCE1 regulates Rho GTPase activity and cell migration through interacting with NCK2 and that PLCE1 also plays a role in the proliferation and differentiation of podocytes, regardless of the presence of NCK2.
Highlights
Filtration is an important function of the kidneys, and the human kidney contains one million glomeruli
steroid-resistant nephrotic syndromes (SRNSs) is accompanied by the rearrangement of the actin cytoskeleton and simplification of interdigitating cellular processes of podocytes, called foot process effacement, which is a classic feature of proteinuric kidney diseases, including SRNS7
As Rac[1], Cdc[42], and RhoA are implicated in the pathogenesis of nephrotic syndrome in mice and humans[16,17,18,19,20], we examined whether these Rho GTPases interact with PLCE1 in cultured podocytes
Summary
Filtration is an important function of the kidneys, and the human kidney contains one million glomeruli (filtering units). The foot processes are in direct contact with the urinary side of the glomerular basement membrane and interdigitate with the foot processes from neighboring cells through specialized intercellular junctions (the ‘slit diaphragm’), thereby forming sieve-like structures that prevent the loss of plasma proteins into the urine[1]. This structure serves to create a maximal filtration. Defects in the glomerular filter result in nephrotic syndrome, a kidney disease characterized by albumin loss (proteinuria). A significant proportion of steroid-resistant nephrotic syndromes (SRNSs) have a genetic background and result from a single-gene defect. SRNS is accompanied by the rearrangement of the actin cytoskeleton and simplification of interdigitating cellular processes of podocytes, called foot process effacement, which is a classic feature of proteinuric kidney diseases, including SRNS7
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