Prevention of kidney ischemia/reperfusion-induced functional injury and JNK, p38, and MAPK kinase activation by remote ischemic pretreatment

MAPK activities, including JNK, p38, and ERK, are markedly enhanced after i schemia in vivo and chemical anoxia in vitro. The relative extent of JNK, p 38, or ERK activation has been proposed to determine cell fate after injury . A mouse model was established in which prior exposure to ischemia protect ed against a second ischemic insult imposed 8 or 15 days later, In contrast to what was observed after 30 min of bilateral ischemia, when a second per iod of ischemia of 30- or 35-min duration was imposed 8 days later, there w as no subsequent increase in plasma creatinine, decrease in glomerular filt ration rate, or increase in fractional excretion of sodium. A shorter perio d of prior ischemia (15 min) was partially protective against subsequent is chemic injury 8 days later. Unilateral ischemia was also protective against a subsequent ischemic insult to the same kidney, revealing that systemic u remia is not necessary for protection. The ischemia-related activation of J NK and p38 and outer medullary vascular congestion were markedly mitigated by prior exposure to ischemia, whereas preconditioning had no effect on pos t-ischemic activation of ERK1/2. The phosphorylation of MKK7, MKK4, and MKK 3/6, upstream activators of JNK and p38, was markedly reduced by ischemic p reconditioning, whereas the post-ischemic phosphorylation of MEK1/2, the up stream activator of ERK1/2, was unaffected by preconditioning. Pre- and pos t-ischemic HSP-25 levels were much higher in the preconditioned kidney. In summary, post-ischemic JNK and p38 (but not ERK1/2) activation was markedly reduced in a model of kidney ischemic preconditioning that was established in the mouse. The reduction in JNK and p38 activation can be accounted for by reduced activation of upstream MAPK kinases. The post-ischemic activati on patterns of MAPKs may explain the remarkable protection against ischemic injury observed in this model.