Treatment with a Novel Hypoxia-Inducible Factor Hydroxylase Inhibitor (TRC160334) Ameliorates Ischemic Acute Kidney Injury

Abstract

Background: Hypoxia-inducible factor (HIF) transcriptional system plays a central role in cellular adaptation to low oxygen levels. Preconditional activation of HIF and/or expression of its individual target gene products leading to cytoprotection have been well established in hypoxic/ischemic renal injury. Increasing evidence indicate HIF activation is involved in hypoxic/ischemic postconditioning of heart, brain and kidney. Very few studies evaluated the potential benefits of postischemia HIF activation in renal injury employing a pharmacological agent. We hypothesized that postischemia augmentation of HIF activation with a pharmacological agent would protect renal ischemia/reperfusion injury. For this, TRC160334, a novel HIF hydroxylase inhibitor, was used. Methods: TRC160334, a novel HIF hydroxylase inhibitor, was synthesized. Ability of TRC160334 for stabilization of HIF-α and consequent HIF activation was evaluated in Hep3B cells. Efficacy of TRC160334 was evaluated in a rat model of ischemia/reperfusion-induced AKI. Two different treatment protocols were employed, one involved treatment with TRC160334 before onset of ischemia, the other involved treatment after the reperfusion of kidneys. Results: TRC160334 treatment results in stabilization of HIF-α leading to HIF activation in Hep3B cells. Significant reduction in renal injury was observed by both treatment protocols and remarkable reduction in serum creatinine (23 and 71% at 24 and 48 h, respectively, p < 0.01) was observed with TRC160334 treatment applied after reperfusion. Urine output was significantly improved up to 24 h by both treatment protocols. Conclusion: The data presented here provide pharmacologic evidence for postischemia augmentation of HIF activation by TRC160334 as a promising and clinically feasible strategy for the treatment of renal ischemia/reperfusion injury.

HIF-1α induction during reperfusion avoids maladaptive repair after renal ischemia/reperfusion involving miR127-3p

“…HIF-1α has been extensively described as a key factor for cell adaptation to hypoxia, including renal tissue19. Consistently with our previous results3 and the findings presented here, the activation of HIF-1α post-ischemia by pharmacological treatment with PHDs inhibitors significantly reduces renal I/R injury20. Pre-ischemic targeting of the PHD/HIF pathway also demonstrated beneficial effect in prevention of chronic renal damage, including fibrosis, subsequent to acute damage6.…”

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…This protective effect was found to be due primarily to the promotion of intestinal epithelial barrier function through the inhibition of apoptosis and the expression of genes that enhance barrier function (46,106). Subsequent studies demonstrated a broader antiinflammatory effect of pharmacological hydroxylase inhibition in diseases such as ischemic acute kidney injury and sepsis, leading to the conclusion that other mechanisms of therapeutic action may also be involved (65,107). Indeed, recent studies have implicated hydroxylase inhibitors in the suppression of cytokine-activated NF-κB-dependent proinflammatory pathways, which may underpin a more general antiinflammatory effect of these drugs (64).…”

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

“…TRC150094 9 , a mimetic of diiodothyronine (T2) (T2 mimetic),16, 85 for the treatment of cardiometabolic risks is currently undergoing Phase 2 studies. TRC160334 10 , a hypoxia‐inducible factor (HIF) hydroxylase inhibitor to treat kidney failure and intestinal bowel disease (IBD), is undergoing Phase 1 studies 86. Two more compounds failed at the preclinical stage: TRC‐282,87 a NO donor for cardiovascular disorders, and TRC‐8156,88 a dipeptidyl peptidase‐IV (DPP‐IV) inhibitor for the treatment of diabetes.…”