Metabolic fuels along the nephron: Pathways and intracellular mechanisms of interaction

Abstract

Substrates in large numbers are removed from the blood by the kidney in linear relationship to their arterial concentrations [1, 2]. At normal arterial blood levels, the kidney utilizes significant amounts of free fatty acids, lactate, glutamine, 3-hydroxybutyrate, and citrate. Furthermore, the kidney removes substrates like pyruvate, α-ketoglutarate, glycerol, proline, and some other amino acids of low arterial concentrations. However, when blood levels of these substances increase, their renal uptake rates likewise increase [1, 2]. Metabolic fates of these substrates in the kidney are related intimately to major functions of the kidney including excretion of waste materials, reabsorption of life conserving substances and water, and other important endocrine and metabolic functions.When studied in vitro, the capacity of renal tissue to take up substrates was shown to be far in excess of the rates occurring under in vivo conditions [2]. This indicates that saturation is not reached in vivo due to suboptimal substrate concentrations. For lactate, pyruvate, glutamine, proline, fatty acids, and ketone bodies, normal arterial levels are below or around the half-maximal concentration kinetically determined in in vitro uptake studies [3–8]. However, even under this nonsaturating condition, the rates of substrate uptake in vivo exceed the quantities of fuel needed to meet the energy demands of the kidney as calculated from oxygen uptake [1, 9]. Table 1 summarizes the calculated oxygen uptake and ATP formation rates for some substrates. From the theoretical and the experimental data on substrate uptake rates and measurements of oxygen consumption [1, 2], it becomes clear that the kidney takes up more substrates than could be accounted for by oxidation.The term “incomplete oxidation” was introduced by Cohen [1] to explain this phenomenon. For example, 3-hydroxybutyrate taken up by the kidney is partially released as acetoacetate [8]. On the other hand, no net product release was found for other substrates taken up in excess. From recent in vitro studies, it was concluded that the kidney can utilize substrates by metabolic pathways that do not lead to their oxidation [2–7]. Thus, lactate, glycerol, glutamine, and other substrates are in part converted to glucose through the gluconeogenic pathway, whereas fatty acids which cannot be converted to glucose are recovered mainly as triacylglycerol [5, 10].Two major questions may be raised at this point: (1) What nephron cells are responsible for the substrate uptake rates observed? (2) What are the mechanisms regulating intracellular interactions of various substrates?This review will briefly summarize some recent findings on intercellular heterogeneity and intracellular regulatory mechanisms that may help explain the metabolic balances observed in vivo