Toll-Like Receptor 4 Induction During Renal Ischemia Correlates with Serum Creatinine in a Pig Model.

To determine whether toll-like receptor 4 (TLR4), a mediator of organ ischemia-reperfusion injury, is overexpressed during warm ischemia in a porcine solitary kidney model, and whether its expression correlates with creatinine, a surrogate for kidney function. Eight adult Yorkshire pigs underwent initial laparoscopic nephrectomy. After 1 week, animals were randomized into two groups: group 1 underwent laparoscopic renal hilar dissection, renal ischemia by cross-clamping, and reperfusion (ischemia group); group 2 underwent laparoscopic renal hilar dissection alone (sham group).

TLR4 counteracts BVRA signaling in human leukocytes via differential regulation of AMPK, mTORC1 and mTORC2.

TLR4 is implicated in diseases associated with chronic low-grade inflammation, yet homeostatic signaling mechanisms that prevent and/or are affected by chronic TLR4 activation are largely uncharacterized. We recently reported that LPS/TLR4 activates in human leukocytes signaling intermediates (SI), abbreviated TLR4-SI, which include mTORC1-specific effectors and targets, and that leukocytes of patients with T2D or after cardiopulmonary bypass (CPB) expressed similar SI. Extending these previous findings, here we show that TLR4-SI expression post-CPB was associated with low serum bilirubin and reduced preoperative expression of biliverdin reductase A (BVRA), the enzyme that converts biliverdin to bilirubin, in patient's leukocytes.

Insulin-Dependent Regulation of mTORC2-Akt-FoxO Suppresses TLR4 Signaling in Human Leukocytes: Relevance to Type 2 Diabetes.

Leukocyte signaling in patients with systemic insulin resistance is largely unexplored. We recently discovered the presence of multiple Toll-like receptor 4 (TLR4) signaling intermediates in leukocytes from patients with type 2 diabetes or acute insulin resistance associated with cardiopulmonary bypass surgery. We extend this work to show that in addition to matrix metalloproteinase 9, hypoxia-inducible factor 1α, and cleaved AMPKα, patient leukocytes also express IRS-1 phosphorylated on Ser(312), Akt phosphorylated on Thr(308), and elevated TLR4 expression.

Unilateral Partial Nephrectomy with Warm Ischemia Results in Acute Hypoxia Inducible Factor 1-Alpha (HIF-1α) and Toll-Like Receptor 4 (TLR4) Overexpression in a Porcine Model.

Purpose: Ischemia/reperfusion (I/R) during partial nephrectomy (PN) contributes to acute kidney injury (AKI), which is inaccurately assessed using existent clinical markers of renal function. We evaluated I/R-related changes in expression in hypoxia inducible factor 1α (HIF-1α) and toll-like receptor 4 (TLR4), within kidney tissue and peripheral blood leukocytes (PBL) in a porcine model of PN.

Materials And Methods: Three adult pigs each underwent unilateral renal hilar cross clamping for 180 min followed by a 15 min reperfusion.

Proteolytic Cleavage of AMPKα and Intracellular MMP9 Expression Are Both Required for TLR4-Mediated mTORC1 Activation and HIF-1α Expression in Leukocytes.

LPS-induced TLR4 activation alters cellular bioenergetics and triggers proteolytic cleavage of AMPKα and HIF-1α expression in leukocytes. In human leukocytes, and more specifically neutrophils, AMPKα cleavage yields 55- and 35-kDa protein fragments. In this study, we address the mechanism by which AMPKα is cleaved and its relevance to human health.