TY - JOUR
T1 - Tribbles homolog 3 attenuates mammalian target of rapamycin complex-2 signaling and inflammation in the diabetic kidney
AU - Borsting, Emily
AU - Patel, Shalin V.
AU - Declèves, Anne Emilie
AU - Lee, Sarah J.
AU - Rahman, Qazi M.
AU - Akira, Shizuo
AU - Satriano, Joe
AU - Sharma, Kumar
AU - Vallon, Volker
AU - Cunard, Robyn
N1 - Funding Information:
MCT cells were a kind gift from Eric G. Neilson. We also thank Timo Rieg and Nazila Sabri for excellent technical advice and assistance. We would also like to thank Marc Montminy, Salk Institute, and Alexandra Newton, University of California San Diego, for their helpful discussions. These studies were performed with the support of the Department of Veterans Affairs Career Development Transition Award and Merit Award and the University of California San Diego Senate and National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases DRC Pilot and Feasibility Grant P30 DK063491, awarded to R.C. V.V. was supported by NIH grant RO1-DK56248 and the O'Brien Core Center for Acute Kidney Injury Research NIH grant P30-DK079337.
Funding Information:
These studies were performed with the support of the Department of Veterans Affairs Career Development Transition Award and Merit Award and the University of California San Diego Senate and National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases DRC Pilot and Feasibility Grant P30 DK063491, awarded to R.C. V.V. was supported by NIH grant RO1-DK56248 and the O’Brien Core Center for Acute Kidney Injury Research NIH grant P30-DK079337.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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 (Ser473), 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.
AB - 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 (Ser473), 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.
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U2 - 10.1681/ASN.2013070811
DO - 10.1681/ASN.2013070811
M3 - Article
C2 - 24676635
AN - SCOPUS:84921670676
VL - 25
SP - 2067
EP - 2078
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 9
ER -