The relationship between renal metabolism and proximal tubule transport during ontogeny

Abstract

The proximal tubules of newborn and adult animals reabsorb a similar fraction of the filtered load of Na⁺ and H₂O (65%–70%). In tubules from adult animals, transcellular, active Na⁺ reabsorption accounts for one-third of the total, while two-thirds occur passively through the paracellular pathway, driven by hydrostatic and oncotic forces (one-third) and by cell-generated effective osmotic and ionic gradients (one-third). Since two-thirds of the Na⁺ is reabsorbed passively and does not require energy, the mature proximal tubule has a high Na⁺/O₂ molar ratio (48 Eq of Na⁺/mol of O₂). Measurements of ouabain-sensitive oxygen consumption in suspensions of proximal tubules indicate that in newborn, aerobic metabolism can support about 50% of the net Na⁺ transport rate compared with the 33% in tubules from adult animals. Independent confirmation of the direct and proportional relationship between active Na⁺ transport and ouabain-sensitive O₂ consumption exists for the adult but not for the newborn. However, measurements of epithelial conductances and of transepithelial hydrostatic and oncotic pressure differences indicate that passive paracellular fluxes can account for the remaining 50% of the proximal Na⁺ reabsorption in newborn. The high permeability of the proximal tubules of newborn animals to small molecular weight solutes suggests that cell-generated osmotic and ionic transepithelial gradients are minimal in the tubules of newborn animals. Yet in the newborn, the osmolality of the end proximal tubule fluid was found to exceed that in plasma. This indicates that osmotic gradients due to differences in reflection coefficients for preferentially reabsorbed solutes and Cl⁻ do exist across the proximal tubules of the newborn and suggests that these gradients may contribute to Na⁺ and H₂O reabsorption. If this is indeed the case, then the contribution of active and of hydrostatic and oncotic pressure-driven flows to the overall reabsorption of Na⁺ and fluid has been overestimated. Resolution of this discrepancy requires measurements of the reflection coefficients for HCO ⁻₃ and Cl⁻ in the proximal tubule of the newborn. The metabolic processes by which energy is supplied to renal proximal cells during development are also incompletely characterized. There is evidence that maturation of aerobic metabolism, Krebs cycle enzymes activity, and of the mitochondrial membrane surface area precede the development of net reabsorptive transport (Na⁺, H₂O, HCO₃, glucose). By contrast, maturation of Na⁺−K⁺-ATPase activity at the basolateral cell membrane follows that in reabsorptive transport and does not limit its development. The extent to which age-related changes in reabsorptive fluxes are due to the development of luminal membrane transport systems, to the decrease in paracellular permeability, or both remains to be determined. The high activity of enzymes in the hexosemonophosphate pathway and the high NADH/NAD ratio present during the first few weeks of extrauterine life poise the proximal tubules for high rates of biosynthesis of membrane lipids, glycoproteins, nucleic acids, and transporter proteins necessary for final differentiation.