Recent advances in renal epithelial transport
2018; American Physical Society; Volume: 316; Issue: 2 Linguagem: Inglês
10.1152/ajprenal.00510.2018
ISSN1931-857X
Autores Tópico(s)Chronic Kidney Disease and Diabetes
ResumoEditorial FocusRecent advances in renal epithelial transportAnita T. LaytonAnita T. LaytonDepartment of Applied Mathematics and School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada; and Departments of Mathematics, Biomedical Engineering, and Medicine, Duke University, Durham, North CarolinaPublished Online:29 Jan 2019https://doi.org/10.1152/ajprenal.00510.2018This is the final version - click for previous versionMoreSectionsPDF (57 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Besides the excretion of metabolic wastes, the kidneys regulate the balance of sodium, potassium, and acid-base (15). Impairment of certain transport functions is known to play an important role in the pathogenesis of diseases such as proteinuria and hypertension. But despite decades of research, aspects of renal epithelial transport mechanisms have yet to be fully elucidated. This editorial focus will highlight recent advances in our understanding of renal epithelial transport, obtained from experimental and theoretical studies. Some of these studies were published in response to a recent Call for Papers of this journal: Molecular Mechanism of Renal Tubule Transport.PROXIMAL TUBULEThe kidney plays an integral role in glucose homeostasis. The tight control of blood glucose relies, in part, on renal glucose reabsorption, which under physiological conditions takes place primarily along the proximal convoluted tubule and is mediated by the sodium-glucose cotransporter 2 (SGLT2) (19). In a recent study, Coady et al. (2) coexpressed human SGLT2 and human protein MAP17 in Xenopus oocytes to study the activity and kinetics of SGLT2. They reported that SGLT2 has a lower affinity for glucose relative to SGLT1, a transport stoichiometry of 1:1, a substantially higher affinity for phlorizin, and a significant affinity for dapagliflozin in the subnanomolar range.Given the fundamental role of SGLT2 in glucose homeostasis, SGLT2 inhibitors have emerged as a promising therapeutic approach for lowering plasma glucose levels in diabetes (5): SGLT2 inhibitors improve glycemic control by limiting glucose reabsorption along the early proximal tubule and enhancing urinary glucose excretion. In the United States, three SGLT2 inhibitors have been approved: dapagliozin, canagliflozin, and empagliozin. A number of studies have been conducted to enhance our understanding of these drugs. Fu et al. (3) investigated the potential role of organic anion transporter 3 (OAT3) in the renal transport and secretion of empagliozin. Their results, obtained in mice, suggest that glomerular filtration and tubular secretion contribute to similar extents to the urinary excretion of empagliflozin. Tubular secretion of empagliflozin is largely independent of OAT3. However, due to the colocalization of SGLT2 and OAT3, the absence of OAT3 was shown to attenuate the effect of empagliflozin on glucose excretion.Canagliflozin and its effect on plasma uremic toxins were the focus of a study by Mishima et al. (11). In addition to the inhibition of SGLT2, canagliflozin also exerts a modest inhibitory effect on SGLT1. Because SGLT1 is expressed in the S3 segment as well as the intestines, canagliflozin may influence the gastrointestinal environment, which in turn affects the accumulation of uremic toxins. Indeed, Mishima et al. showed that in mice, canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins. Those effects may point to a therapeutic option in chronic kidney disease.In addition to their antihyperglycemic effect, SGLT2 inhibitors have been reported to reduce blood pressure and protect diabetic patients from heart failure (6, 14). Using computational rat kidney models (8, 9), Layton and Vallon (7) explored how SGLT2 inhibition affects renal solute transport in diabetic patients with chronic kidney disease. Simulation results suggest that nephron loss in a diabetic kidney would reduce the glucosuric and blood glucose-lowering effects of SGLT2 inhibition. However, due to the higher glucose delivery to the remaining hyperfiltrating nephrons, nephron loss was predicted to increase paracellular Na+ secretion along the proximal tubule, resulting in enhanced natriuretic, diuretic, and kaliuretic effects. These results may explain the cardiovascular benefits of SGLT2 inhibitors in diabetic patients with chronic kidney disease.A discussion of proximal tubule epithelial transport would not be complete without mentioning the sexually dimorphic patterns in transporter abundance in rodents. Veiras et al. (20) reported that, in comparison to the male, the female Sprague-Dawley rat’s proximal tubule exhibits lower proximal tubule Na+-phosphate cotransporter 2, aquaporin-1, and claudin-2, but a greater distribution of Na+-H+ exchanger 3 (NHE3) at the base of the microvilli. Additionally, Sabolić et al. (17) reported higher mSGLT2 protein abundance level in female Wistar rats compared with males. To understand the functional implications of these findings, Li et al. (10) conducted simulations using sex-specific computational models of solute and transport in the proximal convoluted tubule of the rat kidney. Model simulations predicted that a substantially smaller fraction of the filtered Na+ is reabsorbed by the proximal tubule of the female rat, compared with male. That result can be attributed, primarily, to the smaller transport area and lower NHE3 and claudin-2 (13) expression levels in females. The higher SGLT2 expression in females was predicted to compensate for its lower tubular transport area to achieve a similar hyperglycemic tolerance as that of the male.THICK ASCENDING LIMBThe thick ascending limb reabsorbs 30% of the filtered Na+ load and plays an essential role in Na+ homeostasis. Half of that Na+ is reabsorbed through active transcellular transport, with the remainder via the paracellular pathway. While it is well known that nitric oxide (NO) inhibits thick ascending limb Na+ transport, its effects on segmental Na+ and Cl− permeabilities are poorly understood. To bridge that knowledge gap, Monzon et al. (12) measured transepithelial resistance in isolated perfused thick ascending limbs. They found that NO’s effect on the paracellular pathway reduces net Na+ reabsorption, to a degree similar to its inhibition of transcellular transport.Luminal flow through the thick ascending limb is highly variable. It has been observed that elevations in segmental flow raises Na+ reabsorption along the thick ascending limb by a degree that cannot be explained entirely by increased Na+ delivery. To seek a more complete understanding, Seaz et al. (18) measured Na+-K+-Cl− cotransporter (NKCC2) activity and O2− in perfused isolated thick ascending limbs. Their findings suggest that higher tubular flow stimulates NKCC2 via NOX4 activation and increased O2−, elevating Na+ reabsorption in thick ascending limbs as a consequence.DISTAL CONVOLUTED TUBULEThe thiazide-sensitive Na+-Cl− cotransporter (NCC) is expressed along the distal tubule, where ~10% of filtered Na+ and Cl− is reabsorbed. To further understand the regulation of NCC, which has been hypothesized to involve WNK4 and intracellular [Cl−], Yang et al. (21) generated Wnk4-knockout mice and examined, in knockout and wild-type mice, NCC regulation with low K+ diet and with increased tubular NaCl delivery. Interestingly, their results revealed that WNK4 and [Cl−] are not the only players involved in the regulation of NCC. Indeed, increased NaCl delivery may upregulate NCC via a yet unknown mechanism that can override the inhibition of WNK4 by high [Cl−]. In another study using oocytes, Argaiz et al. (1) showed that, when expressed alone, WNK4 is inhibited by the high cellular [Cl−] and is thus unable to activate STE20-proline-alanine rich kinase (SPAK) and NCC. However, in the presence of a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the sensitivity of WNK4 to [Cl−] is reduced, resulting in the activation of WNK4 and hence SPAK/NCC, despite the high [Cl−].To further facilitate the investigation of NCC function, Rosenbaek et al. (16) generated and characterized an MDCK1 cell line with tetracycline-inducible human NCC expression. Their goal was to develop a single system that 1) would permit a direct comparison between NCC mutants, in terms of their activity or polarized trafficking events, and 2) has intact mammalian intracellular signaling pathways. These authors demonstrated that their polarized MDCK1 cell model allows rapid and direct function assessment between different NCC mutants.CURRENT METHODOLOGIESThis editorial focus will end with a mention of the review by Jaykumar et al. (4), which describes current technologies available for single-molecule labeling of transmembrane proteins. These techniques include fluorescent proteins, chemical tags, acceptor sequence tags, epitope-based tags, fluorogenic tags, fluorescent unnatural amino acid, and tag-free labeling method. Each method has its own pros and cons. Nevertheless, imaging techniques that allow the detecting and tracking of single molecules have the potential to reveal new information in renal transporter trafficking.GRANTSThis research was supported by the Canada 150 Research Chair program and by the National Institutes of Health: National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK-106102.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author.AUTHOR CONTRIBUTIONSA.T.L. drafted manuscript; edited and revised manuscript; approved final version of manuscript.REFERENCES1. Argaiz ER, Chavez-Canales M, Ostrosky-Frid M, Rodríguez-Gama A, Vázquez N, Gonzalez-Rodriguez X, Garcia-Valdes J, Hadchouel J, Ellison D, Gamba G. 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Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation CollectionsAJP-Renal CollectionsMechanisms of Renal Electrolyte Transport and Ion Channel Regulation Cited ByDifferentiated kidney tubular cell-derived extracellular vesicles enhance maturation of tubuloids15 July 2022 | Journal of Nanobiotechnology, Vol. 20, No. 1 More from this issue > Volume 316Issue 2February 2019Pages F274-F276 Copyright & PermissionsCopyright © 2019 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00510.2018PubMed30516422History Received 30 October 2018 Accepted 4 December 2018 Published online 29 January 2019 Published in print 1 February 2019 Metrics
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