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 ( 2/2 ) mice by low-dose streptozotocin, and the mice were followed for 12 weeks.Diabetic TRB3 2/2 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 2/2 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.

Enhanced Osteogenesis of Adipose-Derived Stem Cells by Regulating Bone Morphogenetic Protein Signaling Antagonists and Agonists

“…In addition, the high BMP2 doses required for human osteogenesis are associated with life-threatening inflammatory cervical swelling and adipogenic cyst-like bone formation [44,45]. Interestingly, Trb3 was revealed to inhibit expression of peroxisome proliferator-activated receptor g, a master regulator of adipogenesis, and serves as a negative regulator of proinflammatory cytokines [46][47][48]. The additional knowledge gained from this study may suggest a new complementary osteoinductive strategy using phenamil with noggin suppression to maximize osteogenic differentiation of ASC for bone regeneration and minimize potential adverse effects of current osteoinductive therapeutics.…”

Endoplasmic reticulum stress in kidney function and disease

“…Inhibition of mTORC1 by the specific inhibitor rapamycin protected renal cells from ER stress-induced apoptosis by enhancing autophagic activity [25]. Cunard and colleagues revealed that the expression of TRB3 was upregulated in the diabetic kidney, and that diabetic TRB3 knockout mice induced by streptozotocin developed higher levels of albuminuria and expressed increased levels of ER stress markers in the renal cortices and glomeruli [26]. They found that TRB3 suppressed mTORC1 activity by direct binding and enhanced autophagic activity.…”

Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly

“…TRB3 is an ER stress-associated protein that is upregulated by free fatty acids and ROS through the PERK/CHOP UPR pathway [82]. We recently demonstrated that constitutive knockout of TRB3 worsens albuminuria, cytokine and chemokine expression in murine Type 1 diabetic kidney disease [107], supporting the protective effects of ER stress. Further studies in mice with transgenic and conditional knockouts of key ER stress-associated molecules will likely clarify the roles that these complex pathways play in the diabetic kidney.…”