scholarly journals Physiological role of SLC12 family members in the kidney

2016 ◽  
Vol 311 (1) ◽  
pp. F131-F144 ◽  
Author(s):  
Silvana Bazúa-Valenti ◽  
María Castañeda-Bueno ◽  
Gerardo Gamba
Keyword(s):  
Collecting Duct ◽  
Family Members ◽  
Cell Volume Regulation ◽  
Chloride Concentration ◽  
Physiological Role ◽  
Renal Physiology ◽  
Thick Ascending Limb ◽  
Thiazide Diuretics ◽  
Glucose Reabsorption ◽  
Human Genome Organisation

The solute carrier family 12, as numbered according to Human Genome Organisation (HUGO) nomenclature, encodes the electroneutral cation-coupled chloride cotransporters that are expressed in many cells and tissues; they play key roles in important physiological events, such as cell volume regulation, modulation of the intracellular chloride concentration, and transepithelial ion transport. Most of these family members are expressed in specific regions of the nephron. The Na-K-2Cl cotransporter NKCC2, which is located in the thick ascending limb, and the Na-Cl cotransporter, which is located in the distal convoluted tubule, play important roles in salt reabsorption and serve as the receptors for loop and thiazide diuretics, respectively (Thiazide diuretics are among the most commonly prescribed drugs in the world.). The activity of these transporters correlates with blood pressure levels; thus, their regulation has been a subject of intense research for more than a decade. The K-Cl cotransporters KCC1, KCC3, and KCC4 are expressed in several nephron segments, and their role in renal physiology is less understood but nevertheless important. Evidence suggests that they are involved in modulating proximal tubule glucose reabsorption, thick ascending limb salt reabsorption and collecting duct proton secretion. In this work, we present an overview of the physiological roles of these transporters in the kidney, with particular emphasis on the knowledge gained in the past few years.

Regional and segmental localization of AE2 anion exchanger mRNA and protein in rat kidney

1995 ◽  
Vol 269 (4) ◽  
pp. F461-F468 ◽  
Author(s):  
F. C. Brosius ◽  
K. Nguyen ◽  
A. K. Stuart-Tilley ◽  
C. Haller ◽  
J. P. Briggs ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Rat Kidney ◽  
Chloride Concentration ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
Cortical Collecting Duct ◽  
Base Exchange ◽  
Medullary Thick Ascending Limb ◽  
Nephron Segment ◽  
Medullary Collecting Duct

Chloride/base exchange activity has been detected in every mammalian nephron segment in which it has been sought. However, in contrast to the Cl-/HCO3- exchanger AE1 in type A intercalated cells, localization of AE2 within the kidney has not been reported. We therefore studied AE2 expression in rat kidney. AE2 mRNA was present in cortex, outer medulla, and inner medulla. Semiquantitative polymerase chain reaction of cDNA from microdissected tubules revealed AE2 cDNA levels as follows [copies of cDNA derived per mm tubule (+/- SE)]: proximal convoluted tubule, 688 +/- 161; proximal straight tubule, 652 +/- 189; medullary thick ascending limb, 1,378 +/- 226; cortical thick ascending limb, 741 +/- 24; cortical collecting duct, 909 +/- 71; and outer medullary collecting duct, 579 +/- 132. AE2 cDNA was also amplified in thin limbs and in inner medullary collecting duct. AE2 polypeptide was detected in all kidney regions. AE2 mRNA and protein were also detected in several renal cell lines. The data are compatible with the postulated roles of AE2 in maintenance of intracellular pH and chloride concentration and with its possible participation in transepithelial transport.

scholarly journals Salt-Losing Tubulopathies in Children: What’s New, What’s Controversial?

2017 ◽  
Vol 29 (3) ◽  
pp. 727-739 ◽  
Author(s):  
Robert Kleta ◽  
Detlef Bockenhauer
Keyword(s):  
Clinical Evidence ◽  
Collecting Duct ◽  
Salt Transport ◽  
Renal Physiology ◽  
Thick Ascending Limb ◽  
Rare Disorders ◽  
Clinical Observations ◽  
Tubular Transport ◽  
Molecular Aspects ◽  
Sodium Handling

Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle’s loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.

Localization of the extracellular Ca(2+)-sensing receptor and PTH/PTHrP receptor in rat kidney

1996 ◽  
Vol 271 (4) ◽  
pp. F951-F956 ◽  
Author(s):  
D. Riccardi ◽  
W. S. Lee ◽  
K. Lee ◽  
G. V. Segre ◽  
E. M. Brown ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Physiological Role ◽  
Urinary Concentration ◽  
Thick Ascending Limb ◽  
Cortical Collecting Duct ◽  
Medullary Thick Ascending Limb ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Receptor

Using a strategy based on homology to the bovine parathyroid Ca(2+)-sensing receptor previously identified by us (5), we have recently isolated an extracellular, G protein-coupled Ca2+/ polyvalent cation-sensing receptor, RaKCaR (22), from rat kidney. The localization and physiological role(s) of this receptor in the kidney are not well understood. In the present study, we assessed the distribution of mRNAs for RaKCaR and the parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) receptor along the rat nephron by in situ hybridization and reverse transcriptase-polymerase chain reaction of microdissected nephron segments. Our results show that transcripts for both receptors coexpress at glomeruli, proximal convoluted tubule, proximal straight tubule, cortical thick ascending limb, distal convoluted tubule, and cortical collecting duct. In addition, RaKCaR (but not PTH/PTHrP receptor) transcripts were found in the medullary thick ascending limb and outer medullary and inner medullary collecting ducts. These findings raise the possibility of roles for RaKCaR not only in the regulation of divalent mineral reabsorption but also in water reabsorption and urinary concentration. Taken together, our results provide new insights in understanding the effects of hypercalcemia on hormone-stimulated salt and water transport.

Ion concentration changes in renal cells during regulatory volume decrease

1993 ◽  
Vol 265 (1) ◽  
pp. F77-F86 ◽  
Author(s):  
R. Rick
Keyword(s):  
Collecting Duct ◽  
Regulatory Volume Decrease ◽  
Cell Volume Regulation ◽  
Zealand White Rabbit ◽  
Ion Concentration ◽  
Cell Swelling ◽  
Minor Role ◽  
Thick Ascending Limb ◽  
Concentration Changes ◽  
Volume Decrease

Electron-probe microanalysis was employed to follow ion concentration changes during regulatory volume decrease. The measurements were performed on isolated tubule bundles, which were dissected from medullary rays of New Zealand White rabbit kidneys. Cell swelling and subsequent regulatory volume decrease were induced by incubating the bundles in 190 mosM medium; control bundles were incubated in 290 mosM medium. Under both conditions, the detectable ions accounted for approximately 80% of the intracellular osmolarity. All cells lost significant amounts of Na, K, and Cl during cell volume regulation. While in the proximal straight tubule more than one-half of the ions lost were Na and Cl, in principal and intercalated cells of the cortical collecting duct and in the thick ascending limb the losses of Na and Cl played only a minor role. The efflux of Na and K greatly exceeded the Cl efflux, suggesting the loss of an additional undetectable anion (bicarbonate). Separate measurements in the nucleus, cytoplasm, and several cellular organelles revealed some inhomogeneity of the subcellular ion distribution.

Variable imprinting of the heterotrimeric G protein Gsα-subunit within different segments of the nephron

2000 ◽  
Vol 278 (4) ◽  
pp. F507-F514 ◽  
Author(s):  
Lee S. Weinstein ◽  
Shuhua Yu ◽  
Carolyn A. Ecelbarger
Keyword(s):  
Parathyroid Hormone ◽  
Proximal Tubule ◽  
G Protein ◽  
Collecting Duct ◽  
Renal Physiology ◽  
Paternal Allele ◽  
Intracellular Camp ◽  
Thick Ascending Limb ◽  
Maternal Allele ◽  
Heterotrimeric G Protein

The heterotrimeric G protein Gs is required for hormone-stimulated intracellular cAMP generation because it couples hormone receptors to the enzyme adenylyl cyclase. Hormones that activate Gs in the kidney include parathyroid hormone, glucagon, calcitonin, and vasopressin. Recently, it has been demonstrated that the Gsα gene is imprinted in a tissue-specific manner, leading to preferential expression of Gsα from the maternal allele in some tissues. In the kidney, Gsα is imprinted in the proximal tubule but not in more distal nephron segments, such as the thick ascending limb or collecting duct. This most likely explains why in both humans and mice heterozygous mutations in the maternal allele lead to parathyroid hormone resistance in the proximal tubule whereas mutations in the paternal allele do not. In contrast, heterozygous mutations have little effect on vasopressin action in the collecting ducts. In mice with heterozygous null Gsα mutations (both those with mutations on the maternal or paternal allele), expression of the Na-K-2Cl cotransporter was decreased in the thick ascending limb, suggesting that its expression is regulated by cAMP. The Gsα genes also generate alternative, oppositely imprinted transcripts encoding XLαs, a Gsα isoform with a long NH2-terminal extension, and NESP55, a chromogranin-like neurosecretory protein. The role, if any, of these proteins in renal physiology is unknown.

Dependency of Microdissected Nephron Segments upon Oxidative Phosphorylation and Exogenous Substrates: A Relationship between Tubular Anatomical Location in the Kidney and Metabolic Activity

1989 ◽  
Vol 77 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Shozo Torikai
Keyword(s):  
Collecting Duct ◽  
Anatomical Location ◽  
Thick Ascending Limb ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Nephron Segments ◽  
Henle's Loop ◽  
Renal Tubular ◽  
Substrate Deprivation ◽  
Exogenous Substrates

1. In order to examine the possibility of heterogeneity in the dependence of renal tubular cells upon oxidative phosphorylation and exogenous substrates, the effects of antimycin A and substrate deprivation on adenosine 5′-triphosphate (ATP) content were examined in isolated rat nephron segments in vitro at 37°C. 2. Antimycin A (5 μmol/l) caused varying decrements in cell ATP level within 5 min in the following order: proximal tubules > cortical thick ascending limb of Henle's loop (cTAL) > cortical collecting duct (cCD) in the cortex, and thin descending limb of Henle's loop (TDL) > medullary thick ascending limb of Henle's loop (mTAL) > outer medullary collecting duct (omCD) in the inner stripe of the outer medulla. In the thick ascending limb and the collecting duct, the segments located in the cortex were more sensitive than those in the medulla. 3. Substrate deprivation for 30 min markedly decreased the cell ATP content in cortical and medullary proximal tubules and also in medullary TDL, whereas it caused only a slight decrease in cTAL and mTAL with no change in cCD and omCD. 4. Media made hypertonic by the addition of 200 mmol/l NaCl under aerobic conditions, increased the requirement for exogenous substrates in TDL and mTAL, but not in omCD. This stimulation was seen to a lesser extent in media made hypertonic by the addition of mannitol instead of NaCl. 5. Taking into consideration a knowledge of rat kidney architecture and intrarenal gradient of oxygen partial pressure, it is likely that the observed dependency upon both oxygen and exogenous substrates in the renal tubular cells reflects adaptation of such cells to their anatomical location, and to the availability of those substances in situ. Furthermore, extracellular sodium concentration and osmolarity stimulate metabolic requirements to a different extent among the nephron segments.

scholarly journals Modulation of outer medullary NaCl transport and oxygenation by nitric oxide and superoxide

2011 ◽  
Vol 301 (5) ◽  
pp. F979-F996 ◽  
Author(s):  
Aurélie Edwards ◽  
Anita T. Layton
Keyword(s):  
Nitric Oxide ◽  
Active Transport ◽  
Collecting Duct ◽  
Thick Ascending Limb ◽  
Outer Medulla ◽  
Nacl Transport ◽  
Complex Interactions ◽  
Medullary Thick Ascending Limb ◽  
The Impact ◽  
Stimulation Of

We expanded our region-based model of water and solute exchanges in the rat outer medulla to incorporate the transport of nitric oxide (NO) and superoxide (O2−) and to examine the impact of NO-O2− interactions on medullary thick ascending limb (mTAL) NaCl reabsorption and oxygen (O2) consumption, under both physiological and pathological conditions. Our results suggest that NaCl transport and the concentrating capacity of the outer medulla are substantially modulated by basal levels of NO and O2−. Moreover, the effect of each solute on NaCl reabsorption cannot be considered in isolation, given the feedback loops resulting from three-way interactions between O2, NO, and O2−. Notwithstanding vasoactive effects, our model predicts that in the absence of O2−-mediated stimulation of NaCl active transport, the outer medullary concentrating capacity (evaluated as the collecting duct fluid osmolality at the outer-inner medullary junction) would be ∼40% lower. Conversely, without NO-induced inhibition of NaCl active transport, the outer medullary concentrating capacity would increase by ∼70%, but only if that anaerobic metabolism can provide up to half the maximal energy requirements of the outer medulla. The model suggests that in addition to scavenging NO, O2− modulates NO levels indirectly via its stimulation of mTAL metabolism, leading to reduction of O2 as a substrate for NO. When O2− levels are raised 10-fold, as in hypertensive animals, mTAL NaCl reabsorption is significantly enhanced, even as the inefficient use of O2 exacerbates hypoxia in the outer medulla. Conversely, an increase in tubular and vascular flows is predicted to substantially reduce mTAL NaCl reabsorption. In conclusion, our model suggests that the complex interactions between NO, O2−, and O2 significantly impact the O2 balance and NaCl reabsorption in the outer medulla.

Intrarenal and Cellular Localization of CLC-K2 Protein in the Mouse Kidney

2001 ◽  
Vol 12 (7) ◽  
pp. 1327-1334 ◽  
Author(s):  
KATSUKI KOBAYASHI ◽  
SHINICHI UCHIDA ◽  
SHUKI MIZUTANI ◽  
SEI SASAKI ◽  
FUMIAKI MARUMO
Keyword(s):  
Cellular Localization ◽  
Collecting Duct ◽  
Type A ◽  
Mouse Kidney ◽  
Thick Ascending Limb ◽  
Intercalated Cells ◽  
Basolateral Membranes ◽  
Nephron Segments ◽  
Henle's Loop ◽  
Distal Tubules

Abstract. CLC-K2, a kidney-specific member of the CLC chloride channel family, is thought to play an important role in the transepithelial Cl- transport in the kidney. This consensus was first reached shortly after it was demonstrated that the mutations of the human CLCNKB gene resulted in Bartter's syndrome type III. To clarify the pathogenesis, the exact intrarenal and cellular localization of CLC-K2 by immunohistochemistry of the Clcnk1-/- mouse kidney were investigated by use of an anti-CLC-K antibody that recognized both CLC-K1 and CLC-K2. CLC-K2 is expressed in the thick ascending limb of Henle's loop and distal tubules, where it is localized to the basolateral membranes. The localization of CLC-K2 to these nephron segments strongly implies that CLC-K2 confers the basolateral chloride conductance in the thick ascending limb of Henle's loop and distal tubules, where Cl- is taken up by the bumetanide-sensitive Na-K-2Cl cotransporter or the thiazide-sensitive Na-Cl cotransporter at the apical membranes. CLC-K2 expression was also shown to extend into the connecting tubule in the basolateral membrane. CLC-K2 was found in basolateral membranes of the type A intercalated cells residing along the collecting duct. This localization strongly suggests that CLC-K2 confers the basolateral conductance in the type A intercalated cells where Cl- is taken up by the anion exchanger in exchange for HCO3- at the basolateral membranes. These aspects of CLC-K2 localization suggest that CLC-K2 is important in Cl- transport in the distal nephron segments.

Polaris, a protein disrupted inorpkmutant mice, is required for assembly of renal cilium

2002 ◽  
Vol 282 (3) ◽  
pp. F541-F552 ◽  
Author(s):  
Bradley K. Yoder ◽  
Albert Tousson ◽  
Leigh Millican ◽  
John H. Wu ◽  
Charles E. Bugg ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Collecting Duct ◽  
Physiological Role ◽  
Duct Cell ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Apical Surface ◽  
Cystic Disease ◽  
Cortical Collecting Duct

Cilia are organelles that play diverse roles, from fluid movement to sensory reception. Polaris, a protein associated with cystic kidney disease in Tg737°rpkmice, functions in a ciliogenic pathway. Here, we explore the role of polaris in primary cilia on Madin-Darby canine kidney cells. The results indicate that polaris localization and solubility change dramatically during cilia formation. These changes correlate with the formation of basal bodies and large protein rafts at the apical surface of the epithelia. A cortical collecting duct cell line has been derived from mice with a mutation in the Tg737 gene. These cells do not develop normal cilia, which can be corrected by reexpression of the wild-type Tg737 gene. These data suggest that the primary cilia are important for normal renal function and/or development and that the ciliary defect may be a contributing factor to the cystic disease in Tg737°rpkmice. Further characterization of these cells will be important in elucidating the physiological role of renal cilia and in determining their relationship to cystic disease.

Long-term regulation of renal Na-dependent cotransporters and ENaC: response to altered acid-base intake

2000 ◽  
Vol 279 (3) ◽  
pp. F459-F467 ◽  
Author(s):  
Gheun-Ho Kim ◽  
Stephen W. Martin ◽  
Patricia Fernández-Llama ◽  
Shyama Masilamani ◽  
Randall K. Packer ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Na Channel ◽  
Thick Ascending Limb ◽  
Acid Base Balance ◽  
Acid Base ◽  
Opposite Pattern ◽  
Α Subunit ◽  
Base Balance ◽  
Acid Loading

Increased systemic acid intake is associated with an increase in apical Na/H exchange in the renal proximal tubule mediated by the type 3 Na/H exchanger (NHE3). Because NHE3 mediates both proton secretion and Na absorption, increased NHE3 activity could inappropriately perturb Na balance unless there are compensatory changes in Na handling. In this study, we use semiquantitative immunoblotting of rat kidneys to investigate whether acid loading is associated with compensatory decreases in the abundance of renal tubule Na transporters other than NHE3. Long-term (i.e., 7-day) acid loading with NH4Cl produced large decreases in the abundances of the thiazide-sensitive Na-Cl cotransporter (TSC/NCC) of the distal convoluted tubule and both the β- and γ-subunits of the amiloride-sensitive epithelial Na channel (ENaC) of the collecting duct. In addition, the renal cortical abundance of the proximal type 2 Na-dependent phosphate transporter (NaPi-2) was markedly decreased. In contrast, abundances of the bumetanide-sensitive Na-K-2Cl cotransporter of the thick ascending limb and the α-subunit of ENaC were unchanged. A similar profile of changes was seen with short-term (16-h) acid loading. Long-term (7-day) base loading with NaHCO3resulted in the opposite pattern of response with marked increases in the abundances of the β- and γ-subunits of ENaC and NaPi-2. These adaptations may play critical roles in the maintenance in Na balance when changes in acid-base balance occur.

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