title: Tribbles homolog 3 attenuates mammalian target of rapamycin complex-2 signaling and inflammation in the diabetic kidney.
abstract: The endoplasmic reticulum (ER) stress response is activated in the diabetic kidney and functions to reduce ER protein accumulation and improve cellular function. We previously showed that tribbles homolog 3 (TRB3), an ER stress-associated protein, is upregulated in the diabetic kidney. Here, we investigated whether absence of TRB3 alters outcomes in diabetic nephropathy. Type 1 diabetes was induced in TRB3 wild-type and knockout ((-/-)) mice by low-dose streptozotocin, and the mice were followed for 12 weeks. Diabetic TRB3(-/-) mice developed higher levels of albuminuria and increased expression of inflammatory cytokine and chemokine mRNA in renal cortices relative to wild-type littermates, despite similar hyperglycemia. Diabetic TRB3(-/-) mice also expressed higher levels of ER stress-associated molecules in both the renal cortices and glomeruli. This change was associated with higher renal cortical phosphorylation of AKT at serine 473 (Ser(473)), which is the AKT site phosphorylated by mammalian target of rapamycin complex-2 (mTORC2). We show in renal tubular cells that TRB3 binds to mTOR and the rapamycin-insensitive companion of mTOR (Rictor), a protein specific to mTORC2. Finally, we demonstrate in murine tubular cells that TRB3 can inhibit secretion of IL-6. Thus, TRB3 reduces albuminuria and inflammatory gene expression in diabetic kidney disease by a mechanism that may involve inhibition of the mTORC2/AKT pathway and may prove to be a novel therapeutic target.
authors.affiliation: Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, California;
authors.forename: Emily
authors.initials: E
authors.lastname: Borsting
authors.affiliation: Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, California;
authors.forename: Shalin V
authors.initials: SV
authors.lastname: Patel
authors.affiliation: Center for Renal Translational Medicine, Department of Medicine, University of California San Diego, La Jolla, California; and.
authors.forename: Anne-Emilie
authors.initials: AE
authors.lastname: Declèves
authors.affiliation: Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, California;
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, California;
authors.forename: Qazi M
authors.initials: QM
authors.lastname: Rahman
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, California; Center for Renal Translational Medicine, Department of Medicine, University of California San Diego, La Jolla, California; and.
authors.forename: Joe
authors.initials: J
authors.lastname: Satriano
authors.affiliation: Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, California; Center for Renal Translational Medicine, Department of Medicine, University of California San Diego, La Jolla, California; and.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, California; Center for Renal Translational Medicine, Department of Medicine, University of California San Diego, La Jolla, California; and.
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.affiliation: Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, California; Center for Renal Translational Medicine, Department of Medicine, University of California San Diego, La Jolla, California; and rcunard@ucsd.edu.
authors.forename: Robyn
authors.initials: R
authors.lastname: Cunard
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D015850:Interleukin-6; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C474830:TRB3 protein, mouse; C525637:rictor protein, mouse; D012694:Serine; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases