Journal
CURRENT MEDICINAL CHEMISTRY
Volume 17, Issue 10, Pages 974-986Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/092986710790820642
Keywords
Acute kidney injury; protein tyrosine kinases; tyrphostins; ischemia-reperfusion; sepsis; cisplatin; cyclosporine; nephroprotection
Funding
- FIS [06/0046, PS09/00447, PI061247, PI081564]
- EU [LSHB-CT-2007-036644]
- Sociedad Espanola de Nefrologia [ISCIII-RETIC REDinREN/RD06/0016]
- Comunidad de Madrid [FRACM/SBIO0283/ 2006]
- Programa Intensificacion Actividad Investigadora
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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.
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