title: Blocking rpS6 Phosphorylation Exacerbates Tsc1 Deletion-Induced Kidney Growth.
abstract: The molecular mechanisms underlying renal growth and renal growth-induced nephron damage remain poorly understood. Here, we report that in murine models, deletion of the tuberous sclerosis complex protein 1 (Tsc1) in renal proximal tubules induced strikingly enlarged kidneys, with minimal cystogenesis and occasional microscopic tumorigenesis. Signaling studies revealed hyperphosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and increased phosphorylation of ribosomal protein S6 (rpS6) in activated renal tubules. Notably, knockin of a nonphosphorylatable rpS6 in these Tsc1-mutant mice exacerbated cystogenesis and caused drastic nephron damage and renal fibrosis, leading to kidney failure and a premature death rate of 67% by 9 weeks of age. In contrast, Tsc1 single-mutant mice were all alive and had far fewer renal cysts at this age. Mechanistic studies revealed persistent activation of mammalian target of rapamycin complex 1 (mTORC1) signaling causing hyperphosphorylation and consequent accumulation of 4E-BP1, along with greater cell proliferation, in the renal tubules of Tsc1 and rpS6 double-mutant mice. Furthermore, pharmacologic treatment of Tsc1 single-mutant mice with rapamycin reduced hyperphosphorylation and accumulation of 4E-BP1 but also inhibited phosphorylation of rpS6. Rapamycin also exacerbated cystic and fibrotic lesions and impaired kidney function in these mice, consequently leading to a premature death rate of 40% within 2 weeks of treatment, despite destroying tumors and decreasing kidney size. These findings indicate that Tsc1 prevents aberrant renal growth and tumorigenesis by inhibiting mTORC1 signaling, whereas phosphorylated rpS6 suppresses cystogenesis and fibrosis in Tsc1-deleted kidneys.
authors: Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia;
authors: Huijuan
authors: H
authors: Wu
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors: Jianchun
authors: J
authors: Chen
authors: Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia;
authors: Jinxian
authors: J
authors: Xu
authors: Department of Cellular Biology and Anatomy, Research Department, Charlie Norwood VA Medical Center, Augusta, Georgia; and.
authors: Zheng
authors: Z
authors: Dong
authors: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors: Oded
authors: O
authors: Meyuhas
authors: Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia; jchen@gru.edu.
authors: Jian-Kang
authors: JK
authors: Chen
mesh_terms: D000818:Animals; D017353:Gene Deletion; D007668:Kidney / Q000473:pathology*; D051379:Mice; D010766:Phosphorylation; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D038601:Ribosomal Protein S6; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins
keywords: cystic kidney; kidney growth; molecular signaling to cell growth and proliferation; nephron damage; renal fibrosis; renal proximal tubule cells