AG490 promotes HIF-1α accumulation by inhibiting its hydroxylation.

AG490 is a tyrphostin originally described as a Janus Activated Kinase (JAK) 2 inhibitor. AG490 also inhibits epidermal growth factor receptor (EGFR) and guanylyl cyclases (GC). More recently, AG490 was associated with oxidative stress protection in experimental acute kidney injury models. We now show that AG490 is also a strong activator of the Hypoxia Inducible Factor (HIF)-1. Under normoxic conditions HIF-1α is degraded through hydroxylation, von Hippel Lindau protein (VHL)-mediated ubiquitin tagging and proteasomal degradation. AG490 increased HIF-1α protein, but not HIF-1α mRNA levels, dose- and time-dependently in cultured endothelial, vascular smooth muscle and kidney proximal tubular epithelial cells. AG490 increased HIF-1α protein half-life, suggesting that HIF-1α protein accumulation resulted from a decreased degradation. In this regard, AG490 prevented HIF-1α hydroxylation and increased HIF-1α protein levels in human renal carcinoma cells expressing VHL, but did not further increase HIF-1α in VHL negative cells. AG490 did not prevent the proteasomal degradation of other proteins. HIF-1α was not upregulated by dominant negative JAK2constructs, tyrphostin AG9, the EGFR inhibitors erbstatin and genistein, the GC inhibitor Ly83583 or cGMP analogues. Finally, AG490 also increased HIF-1α transcriptional activity evidenced by the increased HIF-1α-dependent VEGF expression. In conclusion, AG490 is a novel HIF-1α activator that increases HIF-1α half-life and protein levels through interference with HIF-1α hydroxylation and VHL-mediated degradation. This action may contribute to the cell and tissue protective effects of AG490.

Tyrphostins as potential therapeutic agents for acute kidney injury.

Acute kidney injury (AKI) is a syndrome characterized by an acute renal cell injury that leads to sudden loss of renal function. There are currently no clinically validated treatments for AKI besides substituting renal function by dialysis. However, new biomarkers will allow an earlier diagnosis, thus providing a window of opportunity for therapeutic intervention. Tyrphostins are a family of compounds originally designed as protein tyrosine kinase inhibitors. However, some molecules of this family have additional actions, such as inhibition of guanylate and adenylate cyclases, mitochondrial uncoupling or antioxidant effects. We review the potential role of tyrphostins in the prophylaxis and treatment of acute kidney injury on the basis of published studies on animals, in vitro experiments and piecemeal information from humans. The AG 490 and AG 126 tyrphostins have recently been shown to protect from AKI in experimental animal models of ischemia-reperfusion and sepsis-induced injury. AG 490 protects from cyclosporin-induced AKI and AG 1714 protects from cisplatin nephrotoxicity. AG 490 is nephroprotective by inhibiting oxidative stress-related Janus activated kinase-2 (JAK2) activation. Potential applications of AG490 or derivative molecules include AKI of nephrotoxic or ischemic nature, or a combination of both, as may occur in the immediate postransplant period. The molecular targets of AG 126 and AG 1714 are less well characterized. In conclusions, different tyrphostins are nephroprotective in animal models of AKI. The characterization of the molecular targets involved will allow the design of novel therapies that may reach the clinical trial stage.

La aldosterona aumentala calcificación vascularin vitro / Aldosterone increases vascular calcification in in vitro studies

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Papel del VEGF en la respuesta celular a la agresión / Role of VEGF in the cellular response to injury

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