Transport of Amino Acids in the Kidney

Abstract

Amino acids are the building blocks of proteins and key intermediates in the synthesis of biologically important molecules, as well as energy sources, neurotransmitters, regulators of cellular metabolism, etc. The efficient recovery of amino acids from the primary filtrate is a well-conserved key role of the kidney proximal tubule. Additionally, renal metabolism participates in the whole body disposition of amino acids. Therefore, a wide array of axially heterogeneously expressed transporters is localized on both epithelial membranes. For transepithelial transport, luminal uptake, which is carried out mainly by active symporters, is coupled with a mostly passive basolateral efflux. Many transporters require partner proteins for appropriate localization, or to modulate transporter activity, and/or increase substrate supply. Interacting proteins include cell surface antigens (CD98), endoplasmic reticulum proteins (GTRAP3-18 or 41), or enzymes (ACE2 and aminopeptidase N). In the past two decades, the molecular identification of transporters has led to significant advances in our understanding of amino acid transport and aminoacidurias arising from defects in renal transport. Furthermore, the three-dimensional crystal structures of bacterial homologues have been used to yield new insights on the structure and function of mammalian transporters. Additionally, transgenic animal models have contributed to our understanding of the role of amino acid transporters in the kidney and other organs and/or at critical developmental stages. Progress in elucidation of the renal contribution to systemic amino acid homeostasis requires further integration of kinetic, regulatory, and expression data of amino acid transporters into our understanding of physiological regulatory networks controlling metabolism.

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

“…Furthermore, physiological parameters such as blood AA levels support the idea that Xenopus transporters likely evolved in similar environments as mammalian AATs. For example, Leu concentration in Xenopus plasma was reported as 150 μM39 which is consistent with values reported for humans2 and mice40. Additionally, in vitro studies using Xenopus intestines demonstrate similar drug permeabilities as human intestines indicating frog transporter kinetic and substrate specificities mimic human transporter activity41.Salmon SLC6A19/B 0 AT1 expressed in Xenopus oocytes was found to have similar kinetics as mouse B 0 AT142.…”

“…Due to their control over AA transport across barrier membranes, AATs perform crucial roles in AA homeostasis. By mediating intestinal absorption and renal reabsorption, AATs are among the cornerstone regulators of AA bioavailability in humans and other mammals2345. To date, of 52 assigned families of SLCs, eight (SLC 1, 6, 7, 12, 16, 25, 38, 43) are known to have members transporting AAs6.…”

“…In total more than 75 SLC protein species are recognized as AATs6. All AATs function mechanistically by either simple facilitative diffusion (passive transport), or by sym- and/or anti-port of co-substrates such as ions (secondary active transport), and/or the obligatory exchange of AA pairs12. The driving force for vectorial transport is provided by chemical and/or electrical gradients.…”

Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth

“…However, these transporters have kept the ability developed in bacteria to be upregulated in response to nutrient depletion, and in addition, some transporters are transcriptionally induced by HIFs in the nutrient-deprived tumor microenvironment (2,3). Among the many AA transporters identified in human physiology (34,35), at least three AA transporter systems have emerged as playing a major role in the control of growth and cancer aggressiveness if we consider their increased level of expression and correlation with poor disease prognosis. These are the bidirectional EAA transporter complex CD98/LAT1 (SLC5A7) induced by HIF2 (18) and apparently functionally "coupled" to the high-affinity glutamine transporter ASCT2 (SLC1A5; ref.…”

Quantification of 18 Amino Acids in Human Plasma: Application in Renal Transplant Patient Plasma by Targeted UHPLC–MS/MS

“…Amino acid metabolic abnormalities inevitably affected the protein synthesis. It is well known that the kidney is the vital organ to filter, reabsorb and secret the amino acids, which are nearly completely reabsorbed in the proximal convoluted tubule (PCT) to prevent their loss, so as to maintain normal physiological states [29,30]. Up to now, only one previous report discussed the amino acid profile with kidney transplantation (KT), and referred that all amino acids, except tryptophan and arginine reached normal levels in ten children within 72 h after KT, even before in some cases [31].…”