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Journal of the American Society of... Jan 2017
Topics: Endocytosis; Kidney Tubules, Proximal; Metabolic Networks and Pathways; Nutrients; TOR Serine-Threonine Kinases
PubMed: 27789606
DOI: 10.1681/ASN.2016080924 -
American Journal of Physiology. Cell... Sep 2021The fluid in the 14 distinct segments of the renal tubule undergoes sequential transport processes that gradually convert the glomerular filtrate into the final urine.... (Review)
Review
The fluid in the 14 distinct segments of the renal tubule undergoes sequential transport processes that gradually convert the glomerular filtrate into the final urine. The solute carrier (SLC) family of proteins is responsible for much of the transport of ions and organic molecules along the renal tubule. In addition, some SLC family proteins mediate housekeeping functions by transporting substrates for metabolism. Here, we have developed a curated list of SLC family proteins. We used the list to produce resource webpages that map these proteins and their transcripts to specific segments along the renal tubule. The data were used to highlight some interesting features of expression along the renal tubule including sex-specific expression in the proximal tubule and the role of accessory proteins (β-subunit proteins) that are thought to be important for polarized targeting in renal tubule epithelia. Also, as an example of application of the data resource, we describe the patterns of acid-base transporter expression along the renal tubule.
Topics: Animals; Biological Transport; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Glomerulus; Kidney Medulla; Kidney Tubules; Male; Mice; Molecular Sequence Annotation; Organoids; Sex Factors; Single-Cell Analysis; Solute Carrier Proteins
PubMed: 34191628
DOI: 10.1152/ajpcell.00197.2021 -
The Journal of Physiology Sep 2015The reabsorptive activity of renal proximal tubule cells is mediated by receptor-mediated endocytosis and polarized transport systems that reflect final cell... (Review)
Review
KEY POINTS
The reabsorptive activity of renal proximal tubule cells is mediated by receptor-mediated endocytosis and polarized transport systems that reflect final cell differentiation. Loss-of-function mutations of the endosomal chloride-proton exchanger ClC-5 (Dent's disease) cause a major trafficking defect in proximal tubule cells, associated with lysosomal dysfunction, oxidative stress and dedifferentiation/proliferation. A similar but milder defect is associated with mutations in CFTR (cystic fibrosis transmembrane conductance regulator). Vesicular chloride transport appears to be important for the integrity of the endolysosomal pathway in epithelial cells.
ABSTRACT
The epithelial cells lining the proximal tubules of the kidney reabsorb a large amount of filtered ions and solutes owing to receptor-mediated endocytosis and polarized transport systems that reflect final cell differentiation. Dedifferentiation of proximal tubule cells and dysfunction of receptor-mediated endocytosis characterize Dent's disease, a rare disorder caused by inactivating mutations in the CLCN5 gene that encodes the endosomal chloride-proton exchanger, ClC-5. The disease is characterized by a massive urinary loss of solutes (renal Fanconi syndrome), with severe metabolic complications and progressive renal failure. Investigations of mutations affecting the gating of ClC-5 revealed that the proximal tubule dysfunction may occur despite normal endosomal acidification. In addition to defective endocytosis, proximal tubule cells lacking ClC-5 show a trafficking defect in apical receptors and transporters, as well as lysosomal dysfunction and typical features of dedifferentiation, proliferation and oxidative stress. A similar but milder defect is observed in mouse models with defective CFTR, a chloride channel that is also expressed in the endosomes of proximal tubule cells. These data suggest a major role for endosomal chloride transport in the maintenance of epithelial differentiation and reabsorption capacity of the renal proximal tubule.
Topics: Animals; Chloride Channels; Chlorides; Endocytosis; Endosomes; Epithelial Cells; Humans; Ion Transport; Kidney Tubules, Proximal
PubMed: 25820368
DOI: 10.1113/JP270087 -
The American Journal of Cardiology Dec 2019Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given... (Review)
Review
Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.
Topics: Diabetes Mellitus, Type 2; Disease Progression; Glomerular Filtration Rate; Humans; Kidney; Kidney Tubules; Kidney Tubules, Distal; Kidney Tubules, Proximal; Nitric Oxide Synthase; Renal Circulation; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchanger 3
PubMed: 31741437
DOI: 10.1016/j.amjcard.2019.10.027 -
American Journal of Physiology. Renal... Oct 2008Claudins are a family of tight junction membrane proteins that regulate paracellular permeability of epithelia, likely by forming the lining of the paracellular pore.... (Review)
Review
Claudins are a family of tight junction membrane proteins that regulate paracellular permeability of epithelia, likely by forming the lining of the paracellular pore. Claudins are expressed throughout the renal tubule, and mutations in two claudin genes are now known to cause familial hypercalciuric hypomagnesemia with nephrocalcinosis. In this review, we discuss recent advances in our understanding of the physiological role of various claudins in normal kidney function, and in understanding the fundamental biology of claudins, including the molecular basis for selectivity of permeation, claudin interactions in tight junction formation, and regulation of claudins by protein kinases and other intracellular signals.
Topics: Amino Acid Sequence; Animals; Claudin-1; Humans; Kidney Tubules; Membrane Proteins; Molecular Sequence Data; Multigene Family; Protein Structure, Tertiary; Tight Junctions
PubMed: 18480174
DOI: 10.1152/ajprenal.90264.2008 -
Experimental Biology and Medicine... Apr 2017Calcium is vital for many physiological functions including bone mineralization. Postnatal deposition of calcium into bone is greatest in infancy and continues through... (Review)
Review
Calcium is vital for many physiological functions including bone mineralization. Postnatal deposition of calcium into bone is greatest in infancy and continues through childhood and adolescence until peek mineral density is reached in early adulthood. Thereafter, bone mineral density remains static until it eventually declines in later life. A positive calcium balance, i.e. more calcium absorbed than excreted, is crucial to bone deposition during growth and thus to peek bone mineral density. Dietary calcium is absorbed from the intestine into the blood. It is then filtered by the renal glomerulus and either reabsorbed by the tubule or excreted in the urine. Calcium can be (re)absorbed across intestinal and renal epithelia via both transcellular and paracellular pathways. Current evidence suggests that significant intestinal and renal calcium transport changes occur throughout development. However, the molecular details of these alterations are incompletely delineated. Here we first briefly review the current model of calcium transport in the intestine and renal tubule in the adult. Then, we describe what is known with regard to calcium handling through postnatal development, and how alterations may aid in mediating a positive calcium balance. The role of transcellular and paracellular calcium transport pathways and the contribution of specific intestinal and tubular segments vary with age. However, the current literature highlights knowledge gaps in how specifically intestinal and renal calcium (re)absorption occurs early in postnatal development. Future research should clarify the specific changes in calcium transport throughout early postnatal development including mediators of these alterations enabling appropriate bone mineralization. Impact statement This mini review outlines the current state of knowledge pertaining to the molecules and mechanisms maintaining a positive calcium balance throughout postnatal development. This process is essential to achieving optimal bone mineral density in early adulthood, thereby lowering the lifetime risk of osteoporosis.
Topics: Age Factors; Animals; Biological Transport; Bone Density; Calcium, Dietary; Humans; Intestinal Absorption; Intestinal Mucosa; Intestines; Kidney Tubules
PubMed: 28346014
DOI: 10.1177/1535370217699536 -
American Journal of Physiology. Renal... May 2004The evolution of the vertebrate kidney records three occasions, each separated by about 50 million years, when fish have abandoned glomeruli to produce urine by tubular... (Review)
Review
The evolution of the vertebrate kidney records three occasions, each separated by about 50 million years, when fish have abandoned glomeruli to produce urine by tubular mechanisms. The recurring dismissal of glomeruli suggests a mechanism of aglomerular urine formation intrinsic to renal tubules. Indeed, the transepithelial secretion of organic solutes and of inorganic solutes such as sulfate, phosphate, and magnesium can all drive secretory water flow in renal proximal tubules of fish. However, the secretion of NaCl via secondary active transport of Cl is the primary mover of secretory water flow in, surprisingly, proximal tubules of both glomerular and aglomerular fish. In filtering kidneys, the tubular secretion of solute and water is overshadowed by reabsorptive transport activities, but secretion progressively comes to light as glomerular filtration decreases. Thus the difference between glomerular and aglomerular urine formation is more a difference of degree than of kind. At low rates of glomerular filtration in seawater fish, NaCl-coupled water secretion serves to increase the renal excretory capacity by increasing the luminal volume into which waste, excess, and toxic solutes can be secreted. The reabsorption of NaCl and water in the distal nephron and urinary bladder concentrates unwanted solutes for excretion while minimizing renal water loss. In aglomerular fish, NaCl-coupled water secretion across proximal tubules replaces glomerular filtration to increase renal excretory capacity. A review of the literature suggests that tubular secretion of NaCl and water is an early function of the vertebrate proximal tubule that has been retained throughout evolution. Active transepithelial Cl secretion takes place in gall bladders studied as models of the mammalian proximal tubule and in proximal tubules of amphibians and apparently also of mammals. The tubular secretion of Cl is also observed in mammalian distal tubules. The evidence consistent with and for Cl secretion in, respectively, proximal and distal tubules of the mammalian kidney calls for a reexamination of basic assumptions in renal physiology that may lead to new opportunities for managing some forms of renal disease.
Topics: Adaptation, Physiological; Animals; Biological Evolution; Fishes; Kidney Glomerulus; Kidney Tubules; Water-Electrolyte Balance
PubMed: 15075177
DOI: 10.1152/ajprenal.00351.2003 -
American Journal of Physiology. Renal... Jun 2017Calcium (Ca) and Magnesium (Mg) reabsorption along the renal tubule is dependent on distinct trans- and paracellular pathways. Our understanding of the molecular... (Review)
Review
Calcium (Ca) and Magnesium (Mg) reabsorption along the renal tubule is dependent on distinct trans- and paracellular pathways. Our understanding of the molecular machinery involved is increasing. Ca and Mg reclamation in kidney is dependent on a diverse array of proteins, which are important for both forming divalent cation-permeable pores and channels, but also for generating the necessary driving forces for Ca and Mg transport. Alterations in these molecular constituents can have profound effects on tubular Ca and Mg handling. Diuretics are used to treat a large range of clinical conditions, but most commonly for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate sodium (Na) transport, but also indirectly affect renal Ca and Mg handling, i.e., by establishing a prerequisite electrochemical gradient. It is therefore not surprising that substantial alterations in divalent cation handling can be observed following diuretic treatment. The effects of diuretics on renal Ca and Mg handling are reviewed in the context of the present understanding of basal molecular mechanisms of Ca and Mg transport. Acetazolamide, osmotic diuretics, Na/H exchanger (NHE3) inhibitors, and antidiabetic Na/glucose cotransporter type 2 (SGLT) blocking compounds, target the proximal tubule, where paracellular Ca transport predominates. Loop diuretics and renal outer medullary K (ROMK) inhibitors block thick ascending limb transport, a segment with significant paracellular Ca and Mg transport. Thiazides target the distal convoluted tubule; however, their effect on divalent cation transport is not limited to that segment. Finally, potassium-sparing diuretics, which inhibit electrogenic Na transport at distal sites, can also affect divalent cation transport.
Topics: Animals; Biological Transport; Calcium; Diuretics; Epithelial Cells; Humans; Kidney Tubules; Magnesium; Renal Reabsorption
PubMed: 28274923
DOI: 10.1152/ajprenal.00032.2017 -
American Journal of Physiology. Renal... Dec 2010The role of mechanical forces in the regulation of glomerulotubular balance in the proximal tubule (PT) and Ca(2+) signaling in the distal nephron was first recognized a... (Review)
Review
The role of mechanical forces in the regulation of glomerulotubular balance in the proximal tubule (PT) and Ca(2+) signaling in the distal nephron was first recognized a decade ago, when it was proposed that the microvilli in the PT and the primary cilium in the cortical collecting duct (CCD) acted as sensors of local tubular flow. In this review, we present a summary of the theoretical models and experiments that have been conducted to elucidate the structure and function of these unique apical structures in the modulation of Na(+), HCO(3)(-), and water reabsorption in the PT and Ca(2+) signaling in the CCD. We also contrast the mechanotransduction mechanisms in renal epithelium with those in other cells in which fluid shear stresses have been recognized to play a key role in initiating intracellular signaling, most notably endothelial cells, hair cells in the inner ear, and bone cells. In each case, small hydrodynamic forces need to be greatly amplified before they can be sensed by the cell's intracellular cytoskeleton to enable the cell to regulate its membrane transporters or stretch-activated ion channels in maintaining homeostasis in response to changing flow conditions.
Topics: Animals; Bicarbonates; Cells, Cultured; Dogs; Epithelial Cells; Kidney Cortex; Kidney Tubules, Collecting; Kidney Tubules, Proximal; Mechanotransduction, Cellular; Mice; Microvilli; Models, Animal; Sodium
PubMed: 20810611
DOI: 10.1152/ajprenal.00453.2010 -
Seminars in Nephrology May 2016Many common renal insults such as ischemia and toxic injury primarily target the tubular epithelial cells, especially the highly metabolically active proximal tubular... (Review)
Review
Many common renal insults such as ischemia and toxic injury primarily target the tubular epithelial cells, especially the highly metabolically active proximal tubular segment. Tubular epithelial cells are particularly dependent on autophagy to maintain homeostasis and respond to stressors. The pattern of autophagy in the kidney has a unique spatial and chronologic signature. Recent evidence has shown that there is complex cross-talk between autophagy and various cell death pathways. This review specifically discusses the interplay between autophagy and cell death in the renal tubular epithelia. It is imperative to review this topic because recent discoveries have improved our mechanistic understanding of the autophagic process and have highlighted its broad clinical applications, making autophagy a major target for drug development.
Topics: Acute Kidney Injury; Apoptosis; Autophagy; Humans; Kidney Tubules; Reperfusion Injury
PubMed: 27339383
DOI: 10.1016/j.semnephrol.2016.03.005