Substrates induce hypoxic injury to medullary thick limbs of isolated rat kidneys

Under certain conditions, excess of substrates may be detrimental to the kidney. In isolated rat kidneys perfused with cell-free medium, oxidative metabolism to support reabsorptive transport in the presence of a limited oxygen supply results in hypoxic injury to medullary thick ascending limbs (mTAL). Since inhibitors of mitochondrial respiration markedly reduced this injury, we evaluated the effects of altering the availability of substrate for oxidative metabolism in the mTAL. Inhibition of glucose utilization with 2-deoxyglucose (50 mM) and simultaneous inhibition of long-chain fatty acid metabolism with 2-tetradecylglycidic acid (10(-4) M) in the absence of exogenous substrates consistently reduced hypoxic cell injury to mTAL. Similarly, the direct inhibition of substrate oxidation by the citric acid cycle with monofluoroacetate (5 mM) also reduced the extent of damage to this nephron segment. Bypassing these metabolic blockades with L-lactate, pyruvate, or alpha-ketoglutarate stimulated renal oxidative metabolism and increased hypoxic damage to mTAL. Enhanced renal metabolism and function (higher renal oxygen consumption, tubular reabsorption of sodium, and glomerular filtration rate) were paradoxically associated with greater damage to mTAL. Thus, when oxygen supply is limited, substrate-supported aerobic metabolic activity for tubular transport may induce hypoxic injury in the renal medulla.