title: Down-regulation of PKHD1 induces cell apoptosis through PI3K and NF-κB pathways.
abstract: Mutations in PKHD1 (polycystic kidney and hepatic disease gene 1) gene cause the autosomal recessive polycystic kidney disease (ARPKD). Fibrocystin/polyductin (FPC), encoded by PKHD1, is a membrane-associated receptor-like protein. Although it is widely accepted that cystogenesis is mostly due to aberrant cell proliferation and apoptosis, it is still unclear how apoptosis is regulated. The aim of this study is to analyze the relationship among apoptosis, phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor κB (NF-κB) in FPC knockdown kidney cells. We show that PKHD1-silenced HEK293 cells demonstrate a higher PI3K/Akt activity. Selective inhibition of PI3K/Akt using LY294002 or wortmannin in these cells increases serum starvation-induced HEK293 cell apoptosis with a concomitant decrease in cell proliferation and higher caspase-3 activity. PI3K/Akt inhibition also leads to increased NF-κB activity in these cells. We conclude that the PI3K/Akt pathway is involved in apoptotic function in PKHD1-silenced cells, and PI3K/Akt inhibition correlates with upregulation of NF-κB activity. These observations provide a potential platform for determining FPC function and therapeutic investigation of ARPKD.
authors.affiliation: Division of Nephrology, Shenzhen People's Hospital, Second Clinical Medical College, Jinan University, Shenzhen 518020, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Sun
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Hu
authors.forename: Xinzhou
authors.initials: X
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000378:metabolism; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; C451750:PKHD1 protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011956:Receptors, Cell Surface; D051028:bcl-2-Associated X Protein; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3