title: Phosphorylation of ribosomal protein S6 mediates compensatory renal hypertrophy.
abstract: The molecular mechanism underlying renal hypertrophy and progressive nephron damage remains poorly understood. Here we generated congenic ribosomal protein S6 (rpS6) knock-in mice expressing nonphosphorylatable rpS6 and found that uninephrectomy-induced renal hypertrophy was significantly blunted in these knock-in mice. Uninephrectomy-induced increases in cyclin D1 and decreases in cyclin E in the remaining kidney were attenuated in the knock-in mice compared with their wild-type littermates. Uninephrectomy induced rpS6 phosphorylation in the wild-type mice; however, no rpS6 phosphorylation was detected in uninephrectomized or sham-operated knock-in mice. Nonetheless, uninephrectomy stimulated comparable 4E-BP1 phosphorylation in both knock-in and wild-type mice, indicating that mTORC1 was still activated in the knock-in mice. Moreover, the mTORC1 inhibitor rapamycin prevented both rpS6 and 4E-BP1 phosphorylation, significantly blunted uninephrectomy-induced renal hypertrophy in wild-type mice, but did not prevent residual renal hypertrophy despite inhibiting 4E-BP1 phosphorylation in uninephrectomized knock-in mice. Thus, both genetic and pharmacological approaches unequivocally demonstrate that phosphorylated rpS6 is a downstream effector of the mTORC1-S6K1 signaling pathway mediating renal hypertrophy. Hence, rpS6 phosphorylation facilitates the increase in cyclin D1 and decrease in cyclin E1 that underlie the hypertrophic nature of uninephrectomy-induced kidney growth.
authors.affiliation: Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Jinxian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Chen
authors.affiliation: 1] Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA [2] Research Department, Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Meyuhas
authors.affiliation: 1] Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA [2] Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D005260:Female; D055879:Gene Knock-In Techniques; D006984:Hypertrophy / Q000209:etiology / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009392:Nephrectomy / Q000009:adverse effects; D015513:Oncogene Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C530105:Ccnd1 protein, mouse; D018797:Cell Cycle Proteins; D019927:Cyclin E; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D015513:Oncogene Proteins; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; C568314:cyclin E1, mouse; D019938:Cyclin D1; D000076222:Mechanistic Target of Rapamycin Complex 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D020123:Sirolimus