Role of SLC26-Mediated Cl− /Base Exchange in Proximal Tubule NaCl Transport

2008 ◽  
pp. 148-163 ◽  
Author(s):  
Peter S. Aronson
Keyword(s):  
Proximal Tubule ◽  
Nacl Transport ◽  
Base Exchange

Essential role of NHE3 in facilitating formate-dependent NaCl absorption in the proximal tubule

2001 ◽  
Vol 281 (2) ◽  
pp. F288-F292 ◽  
Author(s):  
Tong Wang ◽  
Chao-Ling Yang ◽  
Thecla Abbiati ◽  
Gary E. Shull ◽  
Gerhard Giebisch ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Brush Border Membrane ◽  
Cell Model ◽  
Nacl Transport ◽  
Nacl Absorption ◽  
A Cell ◽  
Complete Dependence ◽  
Stimulation Of

The absorption of NaCl in the proximal tubule is markedly stimulated by formate. This stimulation of NaCl transport is consistent with a cell model involving Cl−-formate exchange in parallel with pH-coupled formate recycling due to nonionic diffusion of formic acid or H+-formate cotransport. The formate recycling process requires H+ secretion. Although Na+-H+ exchanger isoform NHE3 accounts for the largest component of H+ secretion in the proximal tubule, 40–50% of the rates of HCO[Formula: see text] absorption or cellular H+ extrusion persist in NHE3 null mice. The purpose of the present investigation is to use NHE3 null mice to directly test the role of apical membrane NHE3 in mediating NaCl absorption stimulated by formate. We demonstrate that formate stimulates NaCl absorption in the mouse proximal tubule microperfused in vivo, but the component of NaCl absorption stimulated by formate is absent in NHE3 null mice. In contrast, stimulation of NaCl absorption by oxalate is preserved in NHE3 null mice, indicating that oxalate-stimulated NaCl absorption is independent of Na+-H+ exchange. The virtually complete dependence of formate-induced NaCl absorption on NHE3 activity raises the possibility that NHE3 and the formate transporters are functionally coupled in the brush border membrane.

scholarly journals Characterization of renal NaCl and oxalate transport in Slc26a6−/− mice

2019 ◽  
Vol 316 (1) ◽  
pp. F128-F133 ◽  
Author(s):  
Felix Knauf ◽  
Heino Velazquez ◽  
Victoria Pfann ◽  
Zhirong Jiang ◽  
Peter S. Aronson
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Fractional Excretion ◽  
Wild Type ◽  
Nacl Transport ◽  
Lower Blood ◽  
Urine Oxalate

The apical membrane Cl−/oxalate exchanger SLC26A6 has been demonstrated to play a role in proximal tubule NaCl transport based on studies in microperfused tubules. The present study is directed at characterizing the role of SLC26A6 in NaCl homeostasis in vivo under physiological conditions. Free-flow micropuncture studies revealed that volume and Cl− absorption were similar in surface proximal tubules of wild-type and Slc26a6−/− mice. Moreover, the increments in urine flow rate and sodium excretion following thiazide and furosemide infusion were identical in wild-type and Slc26a6−/− mice, indicating no difference in NaCl delivery out of the proximal tubule. The absence of an effect of deletion of SLC26A6 on NaCl homeostasis was further supported by the absence of lower blood pressure in Slc26a6−/− compared with wild-type mice on normal or low-salt diets. Moreover, raising plasma and urine oxalate by feeding mice a diet enriched in soluble oxalate did not affect mean blood pressure. In contrast to the lack of effect of SLC26A6 deletion on NaCl homeostasis, fractional excretion of oxalate was reduced from 1.6 in wild-type mice to 0.7 in Slc26a6−/− mice. We conclude that, although SLC26A6 is dispensable for renal NaCl homeostasis, it is required for net renal secretion of oxalate.

Stimulation of phosphate transport in the proximal tubule by metabolic substrates

1984 ◽  
Vol 247 (4) ◽  
pp. F582-F587 ◽  
Author(s):  
S. R. Gullans ◽  
P. C. Brazy ◽  
L. J. Mandel ◽  
V. W. Dennis
Keyword(s):  
Proximal Tubule ◽  
Fluid Transport ◽  
Initial Rate ◽  
Tricarboxylic Acid Cycle ◽  
Phosphate Transport ◽  
Glucose Absorption ◽  
Metabolic Substrates ◽  
Tricarboxylic Acid Cycle Intermediates ◽  
Stimulation Of

Studies of phosphate transport in the proximal tubule have recently focused on interactions with cellular metabolism. The present studies demonstrate that two fatty acids, valerate and butyrate, and two tricarboxylic acid cycle intermediates, succinate and malate, stimulate net phosphate transport in the rabbit proximal tubule by 34-117%. Valerate had no effect on the total uptake of inorganic [32P]phosphate into suspensions of proximal tubules but did enhance the initial rate of influx. Net fluid transport was unaffected by these substrates although glucose absorption increased by 10-15% following the addition of either valerate or succinate. Since valerate, butyrate, and succinate are known to stimulate gluconeogenesis and respiration, we evaluated the role of gluconeogenesis in the stimulation of phosphate transport. The addition of 3-mercaptopicolinate (1 mM), an inhibitor of gluconeogenesis, did not alter phosphate transport, nor did it prevent the valerate-induced stimulation of phosphate transport. We conclude that valerate, butyrate, succinate, and malate enhance phosphate transport by the proximal convoluted tubule. This action appears to be unrelated to effects on gluconeogenesis and may be related to close links between phosphate transport and oxidative metabolism.

scholarly journals Functional coupling of the downregulated in adenoma Cl−/base exchanger DRA and the apical Na+/H+ exchangers NHE2 and NHE3

2009 ◽  
Vol 296 (2) ◽  
pp. G202-G210 ◽  
Author(s):  
Mark W. Musch ◽  
Donna L. Arvans ◽  
Gary D. Wu ◽  
Eugene B. Chang
Keyword(s):  
Carbonic Anhydrase ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Intestinal Epithelial Cells ◽  
Functional Coupling ◽  
Intestinal Epithelial ◽  
Colon Cells ◽  
Base Exchange ◽  
Synaptotagmin I

Non-nutrient-dependent salt absorption across the brush-border membrane of intestinal epithelial cells is primarily mediated by coupled apical Na+/H+ (aNHE) and anion exchange transport, with the latter suspected of being mediated by DRA (downregulated in adenoma; SLC26A3) that is defective in congenital chloridorrhea. To investigate DRA in greater detail and determine whether DRA and NHE activities can be coupled, we measured 22Na+ and 36Cl− uptake in Caco2BBE colon cells infected with the tet-off-inducible DRA transgene. Under basal conditions, DRA activity was low in normal and infected Caco2BBE cells in the presence of tetracycline, whereas NHE activities could be easily detected. When apical NHE activity was increased by transfection or serum-induced expression of the aNHE isoforms NHE2 and NHE3, increased 36Cl− uptake was observed. Inhibition of DRA activity by niflumic acid was greater than that by DIDS as well as by the NHE inhibitor dimethylamiloride and the carbonic anhydrase inhibitor methazolamide. DRA activity was largely aNHE-dependent, whereas a component of DRA-independent aNHE uptake continued to be observed. Coupled aNHE and DRA activities were inhibited by increased cellular cAMP and calcium and were associated with synaptotagmin I-dependent, clathrin-mediated endocytosis. In summary, these data support the role of DRA in electroneutral NaCl absorption involving functional coupling of Cl−/base exchange and apical NHE.

scholarly journals Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidney

2010 ◽  
Vol 299 (6) ◽  
pp. F1496-F1506 ◽  
Author(s):  
Alan C. Pao ◽  
Aditi Bhargava ◽  
Francesca Di Sole ◽  
Raymond Quigley ◽  
Xinli Shao ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Proximal Tubule ◽  
Cell Surface Expression ◽  
Thick Ascending Limb ◽  
Proximal Tubule Cells ◽  
Mammalian Kidney ◽  
Tubule Cells ◽  
Exchange Activity

Serum and glucocorticoid-regulated kinase 2 (sgk2) is 80% identical to the kinase domain of sgk1, an important mediator of mineralocorticoid-regulated sodium (Na+) transport in the distal nephron of the kidney. The expression pattern and role in renal function of sgk2 are virtually uncharacterized. In situ hybridization and immunohistochemistry of rodent kidney coupled with real-time RT-PCR of microdissected rat kidney tubules showed robust sgk2 expression in the proximal straight tubule and thick ascending limb of the loop of Henle. Sgk2 expression was minimal in distal tubule cells with aquaporin-2 immunostaining but significant in proximal tubule cells with Na+/H+ exchanger 3 (NHE3) immunostaining. To ascertain whether mineralocorticoids regulate expression of sgk2 in a manner similar to sgk1, we examined sgk2 mRNA expression in the kidneys of adrenalectomized rats treated with physiological doses of aldosterone together with the glucocorticoid receptor antagonist RU486. Northern blot analysis and in situ hybridization showed that, unlike sgk1, sgk2 expression in the kidney was not altered by aldosterone treatment. Based on the observation that sgk2 is expressed in proximal tubule cells that also express NHE3, we asked whether sgk2 regulates NHE3 activity. We heterologously expressed sgk2 in opossum kidney (OKP) cells and measured Na+/H+ exchange activity by Na+-dependent cell pH recovery. Constitutively active sgk2, but not sgk1, stimulated Na+/H+ exchange activity by >30%. Moreover, the sgk2-mediated increase in Na+/H+ exchange activity correlated with an increase in cell surface expression of NHE3. Together, these results suggest that the pattern of expression, regulation, and role of sgk2 within the mammalian kidney are distinct from sgk1 and that sgk2 may play a previously unrecognized role in the control of transtubular Na+ transport through NHE3 in the proximal tubule.

scholarly journals Role of KCNE1-Dependent K+ Fluxes in Mouse Proximal Tubule

2001 ◽  
Vol 12 (10) ◽  
pp. 2003-2011
Author(s):  
VOLKER VALLON ◽  
FLORIAN GRAHAMMER ◽  
KERSTIN RICHTER ◽  
MARKUS BLEICH ◽  
FLORIAN LANG ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Coupled Transport ◽  
Wild Type ◽  
Electrochemical Gradient ◽  
Volume Depletion ◽  
Luminal Membrane ◽  
Clearance Studies ◽  
Electrophysiological Studies ◽  
Kidney Micropuncture

Abstract. The electrochemical gradient for K+ across the luminal membrane of the proximal tubule favors K+ fluxes to the lumen. Here it was demonstrated by immunohistochemistry that KCNE1 and KCNQ1, which form together the slowly activated component of the delayed rectifying K+ current in the heart, also colocalize in the luminal membrane of proximal tubule in mouse kidney. Micropuncture experiments revealed a reduced K+ concentration in late proximal and early distal tubular fluid as well as a reduced K+ delivery to these sites in KCNE1 knockout (-/-), compared with wild-type (+/+) mice. These observations would be consistent with KCNE1-dependent K+ fluxes to the lumen in proximal tubule. Electrophysiological studies in isolated perfused proximal tubules indicated that this K+ flux is essential to counteract membrane depolarization due to electrogenic Na+-coupled transport of glucose or amino acids. Clearance studies revealed an enhanced fractional urinary excretion of fluid, Na+, Cl-, and glucose in KCNE1 -/- compared with KCNE1 +/+ mice that may relate to an attenuated transport in proximal tubule and contribute to volume depletion in these mice, as indicated by higher hematocrit values.

scholarly journals Expression and Role of Parathyroid Hormone-Related Protein in Human Renal Proximal Tubule Cells during Recovery from ATP Depletion

1999 ◽  
Vol 10 (2) ◽  
pp. 238-244
Author(s):  
ADOLFO GARCÍA-OCAÑA ◽  
SUSAN C. GALBRAITH ◽  
SCOTT K. VAN WHY ◽  
KAI YANG ◽  
LINA GOLOVYAN ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Recovery Period ◽  
Ischemic Injury ◽  
Atp Depletion ◽  
Proximal Tubule Cell ◽  
Pthrp Expression ◽  
Human Proximal Tubule Cell

Abstract. Parathyroid hormone (PTH)-related protein (PTHrP) is widely expressed in normal fetal and adult tissues and regulates growth and differentiation in a number of organ systems. Although various renal cell types produce PTHrP, and PTHrP expression in rat proximal renal tubules is upregulated in response to ischemic injury in vivo, the role of PTHrP in the kidney is unknown. To study the effects of injury on PTHrP expression and its consequences in more detail, the immortalized human proximal tubule cell line HK-2 was used in an in vitro model of ATP depletion to mimic in vivo renal ischemic injury. These cells secrete PTHrP into conditioned medium and express the type I PTH/PTHrP receptor. Treatment of confluent HK-2 cells for 2 h with substrate-free, glucose-free medium containing the mitochondrial inhibitor antimycin A (1 μM) resulted in 75% depletion of cellular ATP. After an additional 2 h in glucose-containing medium, cellular ATP levels recovered to approximately 75% of baseline levels. PTHrP mRNA levels, as measured in RNase protection assays, peaked at 2 h into the recovery period (at four times baseline expression). The increase in PTHrP mRNA expression was correlated with an increase in PTHrP protein content in HK-2 cells at 2 to 6 h into the recovery period. Heat shock protein-70 mRNA expression was not detectable under baseline conditions but likewise peaked at 2 h into the recovery period. Treatment of HK-2 cells during the recovery period after injury with an anti-PTHrP(1-36) antibody (at a dilution of 1:250) resulted in significant reductions in cell number and uptake of [3H]thymidine, compared with nonimmune serum at the same titer. Similar results were observed in uninjured HK-2 cells. It is concluded that this in vitro model of ATP depletion in a human proximal tubule cell line reproduces the pattern of gene expression previously observed in vivo in rat kidney after ischemic injury and that PTHrP plays a mitogenic role in the proliferative response after energy depletion.

Abstract P244: Role of the Na-H Exchanger Regulatory Factor 1 (NHERF1) in Hypertension of Aging Animals

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Sathnur Pushpakumar ◽  
Corey J Ketchem ◽  
Michelle T Barati ◽  
Utpal Sen ◽  
Pedro J Jose ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Sodium Intake ◽  
Dietary Sodium ◽  
Brown Norway ◽  
Proximal Tubule Cells ◽  
Left Femoral Artery ◽  
Old Rats ◽  
Dopamine Signaling ◽  
Old Mice

Aging animals develop hypertension when challenged with high salt diet due, in part, to desensitization of dopamine receptors (DR) in renal proximal tubules (RPT). We have demonstrated that NHERF1 associates with DR1 and Na-K ATPase (NKA) and is important for regulation of NKA in RPT. Preliminary data showed loss of NHERF1 expression in 22m old F344 rats. We hypothesized that loss of NHERF1 results in increased blood pressure (BP) and lack of natriuretic response to dopamine (DA) in aging animals. To address this hypothesis, Fischer Brown Norway (FBN) rats (1m, 4m, 12m, and 24m old) were fed diet containing 1% or 8% NaCl for one week and, BP was measured in anesthetized animals using an indwelling left femoral artery catheter. 8% NaCl did not increase BP in 1m or 4 month old rats. By contrast, 8% NaCl diet increased BP in 12m (84.3±3.5 vs 90.8±2.36) and 24m (73.5±7.58 vs 104±1.6) old animals. To determine if lack of NHERF1 is responsible for the increase in BP, we measured BP in 12 m old WT and NHERF1 KO mice. By contrast to WT mice, 8% NaCl diet did not increase BP in NHERF1 KO mice (84±4.9 vs 96.5±3.56 (WT) and 78.2±3.89 vs 81.8±9.2 (NHERF1 KO mice)). To confirm that NHERF1 is required for DA-mediated inhibition of NKA, NKA activity in primary proximal tubule cells (PTC) from young and old mice in culture was measured in the presence or absence of DA. DA decreased NKA activity in PTC from young animals (67.2±3.8 vs 32.7±5.3) but not in PTC from old animals. Transfection of NHERF1 restored NKA regulation by DA in PTC from old rats (58.4±4.2 vs 64.4±4.3 (in untransfected cells) 54.2±3.8 vs 31.1±3.4 (in NHERF1 transfected cells)). We conclude that NHERF1 regulates DA-mediated proximal tubule sodium handling; however, other factors modulate BP response to dietary sodium intake in young and old animals. The contribution of NHERF1 and dopamine signaling to sodium homeostasis requires further study.

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