Abstract
Renal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by ‘tuned’ malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury.
Highlights
Ischemia reperfusion (IR) injury occurs upon the return of an oxygenated blood supply to an organ or tissue following a period of ischemia [1,2]
We investigate the efficacy of two mal onate ester prodrugs, dimethyl malonate (DMM) and diacetoxymethyl malonate (MAM, an acyloxymethyl diester) (Fig. 2b), in targeting suc cinate metabolism during renal IR injury in the mouse
Given the transient increase in tissue malonate concentration produced by the malonate ester-prodrugs administered on reperfusion [33,34], it is likely that the protective ef fects of DMM and MAM demonstrated in this study are due to the in hibition of succinate oxidation by succinate dehydrogenase (SDH) on reperfusion, leading to a reduction in mitochondrial reactive oxygen species (ROS) production
Summary
Ischemia reperfusion (IR) injury occurs upon the return of an oxygenated blood supply to an organ or tissue following a period of ischemia [1,2]. The return of oxygenated blood leads to an increase in the level of injury over and above that which occurs during ischemia alone [1,3]. This is due to the production of reactive oxygen species (ROS) during reperfusion, primarily from mitochondria, which go on to initiate much of the downstream damage leading to organ or tissue injury [4,5].
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