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2014-09-01 - Article/Dans un journal avec peer-review - Anglais - 11 page(s)

Borsting E, Patel SV, Decleves Anne-Emilie , Lee SJ, Rahman QM, Akira S, Satriano J, Sharma K, Vallon V, Cunard R, "Tribbles Homolog 3 Attenuates Mammalian Target of Rapamycin Complex-2 Signaling and Inflammation in the Diabetic Kidney" in Clinical Journal of the American Society of Nephrology, 25, 9, 2067-78

  • Edition : American Society of Nephrology (United States)
  • Codes CREF : Sciences biomédicales (DI3200), Néphrologie - urologie (DI3325), Biologie moléculaire (DI3111), Diabétologie (DI3373), Physiologie pathologique (DI3250), Métabolisme (DI3223)
  • Unités de recherche UMONS : Biochimie métabolique et moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
  • Centres UMONS : Centre de Recherche UMONS-Ambroise Paré (UMHAP)

Abstract(s) :

(Anglais) 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. Copyright © 2014 by the American Society of Nephrology.

Identifiants :
  • DOI : 10.1681/ASN.2013070811