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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.

SUBMITTER: Borsting E

PROVIDER: S-EPMC4147976 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Tribbles homolog 3 attenuates mammalian target of rapamycin complex-2 signaling and inflammation in the diabetic kidney.

Borsting Emily E Patel Shalin V SV Declèves Anne-Emilie AE Lee Sarah J SJ Rahman Qazi M QM Akira Shizuo S Satriano Joe J Sharma Kumar K Vallon Volker V Cunard Robyn R

Journal of the American Society of Nephrology : JASN 20140327 9

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 ...[more]

PMID: 24676635

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Project description:Background and objectivesEmerging evidence from recently published observational studies and an individual patient data meta-analysis shows that mammalian target of rapamycin inhibitor use in kidney transplantation is associated with increased mortality. Therefore, all-cause mortality and allograft loss were compared between use and nonuse of mammalian target of rapamycin inhibitors in patients from Australia and New Zealand, where mammalian target of rapamycin inhibitor use has been greater because of heightened skin cancer risk.Design, setting, participants, & measurementsOur longitudinal cohort study included 9353 adult patients who underwent 9558 kidney transplants between January 1, 1996 and December 31, 2012 and had allograft survival ≥1 year. Risk factors for all-cause death and all-cause and death-censored allograft loss were analyzed by multivariable Cox regression using mammalian target of rapamycin inhibitor as a time-varying covariate. Additional analyses evaluated mammalian target of rapamycin inhibitor use at fixed time points of baseline and 1 year.ResultsPatients using mammalian target of rapamycin inhibitors were more likely to be white and have a history of pretransplant cancer. Over a median follow-up of 7 years, 1416 (15%) patients died, and 2268 (24%) allografts were lost. There was a higher risk of all-cause mortality with time-varying mammalian target of rapamycin inhibitor use (hazard ratio, 1.47; 95% confidence interval, 1.23 to 1.76) as well as in the fixed time model analyses comparing mammalian target of rapamycin inhibitor use at baseline (hazard ratio, 1.54; 95% confidence interval, 1.22 to 1.93) and 1 year (hazard ratio, 1.63; 95% confidence interval, 1.32 to 2.01). Time-varying mammalian target of rapamycin inhibitor use was associated with higher risk of death because of malignancy (hazard ratio, 1.37; 95% confidence interval, 1.09 to 1.71). There were no statistically significant differences in the risk of all-cause (hazard ratio, 0.98; 95% confidence interval, 0.85 to 1.12) and death-censored (hazard ratio, 0.85; 95% confidence interval, 0.69 to 1.03) allograft loss between the mammalian target of rapamycin inhibitor use and nonuse groups in the time-varying model as well as the fixed time models.ConclusionsMammalian target of rapamycin inhibitor use was associated with a higher risk of all-cause mortality but not allograft loss.

Dataset Information

Tribbles homolog 3 attenuates mammalian target of rapamycin complex-2 signaling and inflammation in the diabetic kidney.

Publications

Tribbles homolog 3 attenuates mammalian target of rapamycin complex-2 signaling and inflammation in the diabetic kidney.

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