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

Emily Borsting, Shalin V. Patel, Anne Emilie Declèves, Sarah J. Lee, Qazi M. Rahman, Shizuo Akira, Joe Satriano, Kumar Sharma, Volker Vallon, Robyn Cunard

Research output: Contribution to journalArticle

23 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)2067-2078
Number of pages12
JournalJournal of the American Society of Nephrology
Volume25
Issue number9
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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    Borsting, E., Patel, S. V., Declèves, A. E., Lee, S. J., Rahman, Q. M., Akira, S., Satriano, J., Sharma, K., Vallon, V., & Cunard, R. (2014). Tribbles homolog 3 attenuates mammalian target of rapamycin complex-2 signaling and inflammation in the diabetic kidney. Journal of the American Society of Nephrology, 25(9), 2067-2078. https://doi.org/10.1681/ASN.2013070811