Uric acid heralds ischemic tissue injury to mobilize endothelial progenitor cells.

Understanding the nature of endogenous mechanisms for mobilization of stem/progenitor cells is predicated on the identification of injury-induced substances that are released from a damaged organ and capable of producing a distant effect. Although different substances that mobilize endothelial progenitor cells (EPCs) have been proposed, their potential to signal injury and afford postischemic renoprotection and repair remains obscure. Uric acid (UA) is consistently overproduced by ischemic tissues and has been shown to exert immunomodulatory functions. It was hypothesized that UA and/or its precursors might serve as injury signals that are capable of mobilizing EPCs in acute renal ischemia. Indeed, FVB/NJ mice that were subjected to acute renal ischemia showed a transient surge in UA level in the peripheral blood. Single-dose treatment with UA, as well as acute hyperuricemia induced by the inhibition of uricase, caused a robust mobilization of EPCs, whereas administration of adenosine or inosine seemed to lack this effect. Moreover, pretreatment of mice with a single dose of UA afforded significant renoprotection against ischemic injury. In animals with chronic hyperuricemia (induced by continuous 2-wk treatment with a uricase inhibitor oxonic acid), EPC mobilization was blunted and renoprotective effects were absent. In conclusion, acute elevation of UA acts as "physiologic," fast-acting endogenous mediator of EPC mobilization and renoprotection, consistent with its novel function in pharmacologic preconditioning. Both of these actions are lacking in mice with chronic hyperuricemia. In summary, a transient surge in UA concentration may serve as a universal herald of tissue injury to accelerate the recruitment of EPCs.