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- W2955667025 abstract "We previously reported that mutations in ANLN cause familial focal segmental glomerulosclerosis (FSGS). Anillin is an F-actin binding protein that modulates cell motility and interacts with the phosphoinositide 3-kinase (PI-3K) pathway through the slit diaphragm adaptor protein CD2A-associated Protein (CD2AP). It is unclear how ANLNR431C causes FSGS phenotype. We hypothesized that the mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP and inducing aberrant PI3K/AKT/mTOR signaling. We performed in vitro functional assays using human podocyte cell lines stably expressing ANLNWT or ANLNR431C. We then examined the effects of the mutation in vivo in CRISPR-Cas9 mediated point mutation knock-in mouse model of R431C change (R426C in mice). ANLNR431C mutation induced increased cell migration (p=0.001), enhanced cellular proliferation (p=0.001), and apoptosis (p=0.029) relative to ANLNWT cells. Biochemical characterization showed that this dysregulated podocyte phenotypes is due to hyperactivation of the PI-3K/AKT/mTOR/Rac1 signaling axis and activation of mTOR-driven ER stress in the mutant cell line. Podocyte hypermotility, hyperproliferation, and ER stress-induced apoptosis were ameliorated by inhibition of mTOR, GSK-3b, Rac1, or calcineurin (Cn). The R426C CRISPR mice developed significant proteinuria compared to wild type (WT) littermate controls when exposed to low dose nephrotoxic serum. Kidney histology showed protein cast deposition and focal segmental glomerulosclerosis in the mutant mice but not the WT, and increased glomerular size in the mutant mice compared with the WT (p=0.018). Transmission electron microscopy showed widespread effacement of the podocyte foot process in the mutant but not in the WT mice. The ANLNR431C mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. The R426C knock-in mice recapitulated human phenotype following exposure to modest dose of nephrotoxic serum. Further phenotypic characterization and pathway analysis of this mouse model will identify novel therapeutic targets for FSGS due to defective anillin." @default.
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- W2955667025 date "2019-07-01" @default.
- W2955667025 modified "2023-10-08" @default.
- W2955667025 title "SAT-099 ANILLIN (ANLN) MUTATION INITIATES ER-STRESS MEDIATED APOPTOSIS AND INCREASE SUSCEPTIBILITY TO GLOMERULAR INJURY IN MICE" @default.
- W2955667025 doi "https://doi.org/10.1016/j.ekir.2019.05.126" @default.
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