The consequences of increased 4E-BP1 in polycystic kidney disease

• Published in: Human molecular genetics Vol. 28; no. 24; pp. 4132 - 4147
• Main 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.12.2019
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis - drug effects; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Cells, Cultured; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; General - US Office; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Male; Mice; NADH, NADPH Oxidoreductases - metabolism; Phosphorylation; Polycystic Kidney Diseases - metabolism; Polycystic Kidney Diseases - pathology; Polycystic Kidney, Autosomal Dominant - metabolism; Polycystic Kidney, Autosomal Dominant - pathology; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism; Rats; TRPP Cation Channels - metabolism; apoptosis; 4E-BP1; mitochondrial proteins; proliferation; polycystic kidney disease
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddz244

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-BP1F113A and 4E-BP1R13AF113A) would decrease proliferation and reduce cyst expansion. Utilizing the Pkd1RC/RC mouse, we determined the effect of 4E-BP1F113A on PKD. Unexpectedly, 4E-BP1F113A 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.