title: S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal hypertrophy.
abstract: Removal of one kidney stimulates synthesis of RNA and protein, with minimal DNA replication, in all nephron segments of the remaining kidney, resulting in cell growth (increase in cell size) with minimal cell proliferation (increase in cell number). In addition to the compensatory renal hypertrophy caused by nephron loss, pathophysiological renal hypertrophy can occur as a consequence of early uncontrolled diabetes. However, the molecular mechanism underlying renal hypertrophy in these conditions remains unclear. In the present study, we report that deletion of S6 kinase 1 (S6K1) inhibited renal hypertrophy seen following either contralateral nephrectomy or induction of diabetes. In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice. Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2.
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Chen
authors.forename: Jianchun
authors.initials: J
authors.lastname: Chen
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039642:Eukaryotic Initiation Factors; D015971:Gene Expression Regulation, Enzymologic; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy / Q000009:adverse effects; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D004791:Enzyme Inhibitors; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; C448579:ribosomal protein S6, mouse; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020123:Sirolimus