The consequences of increased 4E-BP1 in polycystic kidney disease. (19th October 2019)

• Record Type: Journal Article
• Authors: Holditch, Sara J; Brown, Carolyn N; Atwood, Daniel J; Pokhrel, Deepak; Brown, Sara E; Lombardi, Andrew M; Nguyen, Khoa N; Hill, Ryan C; Lanaspa, Miguel; Hopp, Katharina; Weiser-Evans, Mary C M; Edelstein, Charles L
• Is Part Of: Human molecular genetics. Volume 28:Number 24(2019)
• Page Start: 4132
• Page End: 4147
• Publication Date: 2019-10-19
• Subjects: 4E-BP1 -- polycystic kidney disease -- proliferation -- apoptosis -- mitochondrial proteins; Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddz244
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, characterized by cyst formation and growth. Hyperproliferation is a major contributor to cyst growth. At the nexus of regulating proliferation, is 4E-BP1. We demonstrate that ADPKD mouse and rat models, ADPKD patient renal biopsies and PKD1 −/− cells exhibited hyperphosphorylated 4E-BP1, a biomarker of increased translation and proliferation. We hypothesized that expression of constitutively active 4E-BP1 constructs (4E-BP1 F113A and 4E-BP1 R13AF113A ) would decrease proliferation and reduce cyst expansion. Utilizing the Pkd1 RC/RC mouse, we determined the effect of 4E-BP1 F113A on PKD. Unexpectedly, 4E-BP1 F113A resulted in increased cyst burden and suppressed apoptosis markers, increased anti-apoptotic Bcl-2 protein and increased mitochondrial proteins. Exogenous 4E-BP1 enhanced proliferation, decreased apoptosis, increased anti-apoptotic Bcl-2 protein, impaired NADPH oxidoreductase activity, increased mitochondrial proteins and increased superoxide production in PKD patient-derived renal epithelial cells. Reduced 4E-BP1 expression suppressed proliferation, restored apoptosis and improved cellular metabolism. These findings provide insight into how cyst-lining cells respond to 4E-BP1.