Transport of β-Hydroxy-β-Methyl-Glutarate and β-Hydroxbutyrate by Renal Brushborder Membrane Vesicles

Abstract

SummaryFiltration and subsequent renal tubular reabsorption of this compound could contribute to a state of metabolic acidosis. It was, The Wtake Of P-hydroxy-P-methyl-glutarate (HMG) and P-therefore, of interest to determine the characteristics of renal h~drOx~-but~rate ( PqHB) brushborder membrane brushborder transport in normal animals in order to understand prepared and starved rats was examined. HMG and the mechanism underlying this disorder. The results of these P-HB uptake show a NaC gradient-induced overshoot, suggesting studies form the basis for this report, luminal cotransport of these organic acids. Kinetic analysis of HMG and P-HB uptake revealed a single component carrier svstem and a diffusional component for each compound. Vesicles from starved rats exhibit the same transport characteristics as those from normal rats. The transport interactions of other organic acids with HMG were examined and revealed that citrate is a competitive inhibitor, which implies that the compounds share a common organic acid carrier. SpeculationThe possibility exists that by administration of high oral doses of citrate, urinary citrate can be elevated sufficiently to competitively inhibit the tubular reabsorption of P-hydroxy-P-methyl-glutarate. This, in addition to the buffering properties of citrate, could be of significance in the treatment of the severe metabolic acidosis seen in patients with P-hydroxy-P-methyl-glutarate-CoA lyase deficiency.The compound P-hydroxy-P-methyl-glutaric acid (HMG) is a key intermediate in the metabolic pathways of ketogenesis and cholesterol synthesis. Biosynthesis of HMG, mediated by HMGCoA synthetase, occurs primarily from condensation of two acetoacetyl CoA molecules to form HMG-CoA. Subsequent hydrolysis of the acyl-CoA compound release the free organic acid HMG. Additional HMG-CoA is formed as an intermediate during leucine catabolism. A recent report documenting renal tubular transport of the organic acids citrate and a-ketoglutarate (I I), which are also key metabolic intermediates, stimulated our interest in the renal handling of HMG.The normal hepatic response to fasting is an increased rate of acetoacetyl CoA production, which is reacted with acetyl CoA to form HMG-CoA. The latter compound is then cleaved to release free acetoacetate. Because acetoacetate is normally in equilibrium with P-hydroxy-butyrate (P-HB) in blood, we also examined the transport of P-HB in renal brushborder membrane vesicles. Further, because starvation increases the synthesis rate of both HMG and P-HB, we observed the effects of starvation on the renal transport of these two compounds.The clinical relevance of the present study is underscored by descriptions of children with an inherited deficiency of the enzyme HMG-CoA Ivase, resulting in severe metabolic acidosis and mental retardatidn (5, 6, 20). ?n the face of this enzyme deficiency, large quantities of HMG are produced without further catabolism. MATERIALS AND METHODS Animals.Adult male Sprague-Dawley rats weighing 150-200 g were obtained from Ch...

Renal Clearance of γ-Hydroxybutyric Acid in Rats: Increasing Renal Elimination as a Detoxification Strategy

“…Endogenous short-chain monocarboxylates, such as L-lactate and pyruvate, are freely filtered through the renal glomerulus and almost completely reabsorbed in the proximal tubule, predominantly in their ionized form (Poole and Halestrap, 1993). The saturation of the renal reabsorption of some monocarboxylates, e.g., D-lactate, lactate, pyruvate, acetoacetate, and ␤-hydroxybutyrate, has been well documented in rats (Roth et al, 1982;Barac-Nieto, 1985;Ferrier et al, 1992;Poole and Halestrap, 1993) and rabbits (Nord et al, 1983;Jorgensen and Sheikh, 1985). To our knowledge, there is only one report examining the renal transport of GHB in rabbit brush-border membrane vesicles isolated from the whole cortex, pars convoluta, and pars recta (Jorgensen and Sheikh, 1985).…”

Renal brush-border-membrane vesicles prepared from newborn rats by free-flow electrophoresis and their proline uptake

“…Data obtained from these models have not always been consistent and their interpretation has been uniformly hindered by the difficulties inherent in the study of bipolar transport in renal tubular epithelial cells. Methods for preparation of brush-border-membrane vesicles (Booth & Kenny, 1974) from adult rat kidney have enabled investigators to circumvent this problem in the study of amino acid (McNamara et al, 1976), organic acid (Roth et al, 1982), sugar (Aronson & Sacktor, 1975) and ion (Kinsella & Aronson, 1980) transport. However, application of these methods to study of newborn-rat transport phenomena has not been widely made.…”