AJP - Renal Physiology, Vol 251, Issue 4 710-F717, Copyright © 1986 by American Physiological Society
Substrates induce hypoxic injury to medullary thick limbs of isolated rat kidneys
M. Brezis, S. Rosen, K. Spokes, P. Silva and F. H. Epstein
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.
