Effects of barium ions on tubuloglomerular feedback

1995 ◽  
Vol 268 (5) ◽  
pp. F960-F966 ◽  
Author(s):  
J. Schnermann
Keyword(s):  
Tubuloglomerular Feedback ◽  
K Channel ◽  
Thick Ascending Limb ◽  
Experimental Conditions ◽  
Nacl Transport ◽  
Retrograde Perfusion ◽  
Low Concentrations ◽  
Vasoconstrictor Response ◽  
Nacl Concentration ◽  
Flow Pressure

The furosemide sensitivity of the tubuloglomerular feedback (TGF) response has suggested an important role for the Na-2Cl-K cotransporter in the mechanism by which increased luminal NaCl concentration causes afferent arteriolar vasoconstriction. The present experiments in anesthetized rats were performed to evaluate the effect of K channel blockade with Ba on TGF, since Ba has been shown to inhibit NaCl transport in the thick ascending limb. The presence of either 1.5 or 2 mM BaCl2 during retrograde perfusion with a 135 mM NaCl solution reduced the decrease of early proximal flow rate (VEP) by 2.7 +/- 0.76 (P < 0.02) and 4.2 +/- 0.8 nl/min (P < 0.01) compared with perfusion without BaCl2. Retrograde perfusion with 38 mM NaCl + 5 mM KCl reduced VEP by 10.4 +/- 1.3 nl/min, whereas 40 mM NaCl + 1.5 mM BaCl2 caused a reduction by only 6.1 +/- 1.4 nl/min (P < 0.001). In contrast to the inhibition caused by retrograde perfusion with low concentrations of BaCl2, increased vasoconstriction was seen during retrograde perfusion with 5 mM BaCl2 or during orthograde perfusion with 10 mM BaCl2. The addition of 10(-4) M furosemide to a solution containing 5 mM BaCl2 largely blocked the increased vasoconstrictor response. Peritubular perfusion with a solution containing 5 mM BaCl2 caused a fall in stop-flow pressure in an adjacent nephron by 10.7 +/- 1.5 mmHg (P < 0.001). These results indicate that under our experimental conditions Ba ions exert a dual effect on vascular responses to changes in luminal NaCl concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Potential role of luminal potassium in tubuloglomerular feedback.

1997 ◽  
Vol 8 (12) ◽  
pp. 1831-1837 ◽  
Author(s):  
V Vallon ◽  
H Osswald ◽  
R C Blantz ◽  
S Thomson
Keyword(s):  
Potential Role ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
K Channel ◽  
Thick Ascending Limb ◽  
Retrograde Perfusion ◽  
Luminal Membrane ◽  
K Concentration ◽  
Tubular Flow

Transport through the Na+-2Cl(-)-K+ cotransporter in the luminal membrane of macula densa cells is considered critical for tubuloglomerular feedback (TGF). Although various studies could support the importance of luminal Na+ and Cl-, the role of luminal K+ in TGF has not been thoroughly addressed. The study presented here examines this issue in nephrons with superficial glomeruli of anesthetized male Munich-Wistar-Frömter rats. Ambient Na+ concentration in early distal tubular fluid was approximately 22 mM, suggesting collection sites relatively close to the macula densa segment. First, it was found that ambient early distal tubular K+ concentration is approximately 1.3 mM, i.e., close to the K+ affinity of the Na+-2Cl(-)-K+ cotransporter in the thick ascending limb. Second, it was observed that a change in late proximal tubular flow rate, i.e., a maneuver that is known to induce a TGF response, significantly alters early distal tubular K+ concentration. Third, previous experiments failed to show an inhibition in TGF response during retrograde perfusion of the macula densa with K+-free solutions. Because of a potential K+ influx into the lumen between the perfusion site and the macula densa, however, the K+ channel blocker U37883A was added to the K+-free perfusate. TGF response was assessed as the fall in nephron filtration rate in response to retrograde perfusion of the macula densa segment from early distal tubular site. It was observed that luminal U37883A (100 microM) significantly attenuated TGF. Because adding 5 mM KCl to the perfusate restored TGF in the presence of U37883A and because the inhibitory action of U37883A on tubular K+ secretion was confirmed, the effect of U37883A on TGF was most likely caused by inhibition of K+ influx into the perfused segment, which decreased luminal K+ concentration at the macula densa. The present findings support a potential role for luminal K+ in TGF, which is in accordance with a transmission of the TGF signal across the macula densa via Na+-2Cl(-)-K+ cotransporter.

Effect of dopamine on the tubuloglomerular feedback mechanism

1990 ◽  
Vol 258 (4) ◽  
pp. F790-F798 ◽  
Author(s):  
J. Schnermann ◽  
K. M. Todd ◽  
J. P. Briggs
Keyword(s):  
Flow Rate ◽  
Feedback Mechanism ◽  
Tubuloglomerular Feedback ◽  
Dopamine Infusion ◽  
Vasoconstrictor Response ◽  
Nacl Concentration ◽  
Flow Pressure ◽  
Renal Vascular ◽  
Dose Levels ◽  
Stop Flow

Experiments were performed in anesthetized rats to examine whether infusion of dopamine is associated with a reduction in the tubuloglomerular feedback (TGF) response of stop-flow pressure (PSF) and early proximal flow rate (VEP) to increases of loop of Henle flow. The purpose of these studies was to test further the validity of the proposal that renal vasodilation is a nonspecific cause for diminished TGF responsiveness. When femoral arterial pressure was kept constant with a suprarenal aortic clamp, intravenous infusion of dopamine at rates of 4, 15, 35, and 75 micrograms.kg-1.min-1 induced a 10.9, 23.4, 31.3, and 30.1% decrease in renal vascular resistance. Maximum PSF and VEP responses were significantly reduced at all dose levels of dopamine, whereas V1/2, the flow rate required to produce the half-maximum response, was not altered. TGF blunting occurred within less than 10 min after starting the dopamine infusion. Peritubular infusion of dopamine reduced maximum PSF responses from 8.8 +/- 0.7 to 4.6 +/- 0.53 mmHg at 10(-4) M (P less than 0.01) and from 6.0 +/- 1.19 to 3.6 +/- 0.55 mmHg at 10(-3) M (P less than 0.05). The results are consistent with the notion that renal vasodilatation may modify TGF responses by preventing the full vasoconstrictor response to changes in luminal NaCl concentration.

Nonlinear filter properties of the thick ascending limb

1997 ◽  
Vol 273 (4) ◽  
pp. F625-F634 ◽  
Author(s):  
H. E. Layton ◽  
E. Bruce Pitman ◽  
Leon C. Moore
Keyword(s):  
Steady State ◽  
Frequency Response ◽  
Transit Time ◽  
Concentration Profile ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Transport Parameters ◽  
Nodal Structure ◽  
Nacl Concentration ◽  
Fluid Transit Time

A mathematical model was used to investigate the filter properties of the thick ascending limb (TAL), that is, the response of TAL luminal NaCl concentration to oscillations in tubular fluid flow. For the special case of no transtubular NaCl backleak and for spatially homogeneous transport parameters, the model predicts that NaCl concentration in intratubular fluid at each location along the TAL depends only on the fluid transit time up the TAL to that location. This exact mathematical result has four important consequences: 1) when a sinusoidal component is added to steady-state TAL flow, the NaCl concentration at the macula densa (MD) undergoes oscillations that are bounded by a range interval envelope with magnitude that decreases as a function of oscillatory frequency; 2) the frequency response within the range envelope exhibits nodes at those frequencies where the oscillatory flow has a transit time to the MD that equals the steady-state fluid transit time (this nodal structure arises from the establishment of standing waves in luminal concentration, relative to the steady-state concentration profile, along the length of the TAL); 3) for any dynamically changing but positive TAL flow rate, the luminal TAL NaCl concentration profile along the TAL decreases monotonically as a function of TAL length; and 4) sinusoidal oscillations in TAL flow, except at nodal frequencies, result in nonsinusoidal oscillations in NaCl concentration at the MD. Numerical calculations that include NaCl backleak exhibit solutions with these same four properties. For parameters in the physiological range, the first few nodes in the frequency response curve are separated by antinodes of significant amplitude, and the nodes arise at frequencies well below the frequency of respiration in rat. Therefore, the nodal structure and nonsinusoidal oscillations should be detectable in experiments, and they may influence the dynamic behavior of the tubuloglomerular feedback system.

Dissociation of tubuloglomerular feedback responses from distal tubular chloride concentration in the rat

1981 ◽  
Vol 240 (2) ◽  
pp. F111-F119 ◽  
Author(s):  
P. D. Bell ◽  
C. B. McLean ◽  
L. G. Navar
Keyword(s):  
Chloride Concentration ◽  
Tubuloglomerular Feedback ◽  
Fluid Solution ◽  
Perfusion Rate ◽  
Receptor System ◽  
Retrograde Perfusion ◽  
Perfusion Studies ◽  
Flow Pressure ◽  
Stop Flow ◽  
Feedback Responses

Previous studies have demonstrated that stop-flow pressure (SFP) feedback responses can occur during orthograde perfusion with solutions having low amounts of sodium or chloride. However, retrograde perfusion studies have suggested a specific role for chloride concentration in mediating feedback responses. These studies were conducted to compare SFP feedback responses during orthograde and retrograde perfusion with an artificial tubular fluid solution (ATF) (Cl- = 135 meq/liter) and a Na+ isethionate solution (Cl- = 6 meq/liter). With ATF, increases in perfusion rate from 10 to 35 nl/min led to decreases in SFP of 11 +/- 1.4 mmHg, increases in distal tubular fluid Cl- of 46 +/- 4.9 meq/liter, and osmolality of 58 +/- 10 mosmol/kg. There were significant inverse relationships between SFP and changes in Cl- and osmolality. With Na+ isethionate, SFP decreased by 8.4 +/- 1.0 mmHg, osmolality increased by 43 +/- 8 mosmol/kg, and Cl- did not change. There was a significant relationship between SFP and osmolality, but not with Cl-. During retrograde perfusion at 15 nl/min, SFP decreased by 12 +/- 1.2 mmHg with ATF and by 12 +/- 1.2 mmHg with Na+ isethionate. These results demonstrate that feedback-mediated decreases in SFP can occur in the absence of concomitant increases in distal Cl- and suggest that the receptor system does not have a unique and specific requirement for chloride.

Micropuncture analysis of single-nephron function in NHE3-deficient mice

1999 ◽  
Vol 277 (3) ◽  
pp. F447-F453 ◽  
Author(s):  
John N. Lorenz ◽  
Patrick J. Schultheis ◽  
Timothy Traynor ◽  
Gary E. Shull ◽  
Jürgen Schnermann
Keyword(s):  
Proximal Tubule ◽  
Filtration Rate ◽  
Distal Tubule ◽  
Transport Processes ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Fluid Reabsorption ◽  
Fluid Delivery ◽  
Single Nephron ◽  
Flow Pressure

The Na/H exchanger isoform 3 (NHE3) is expressed in the proximal tubule and thick ascending limb and contributes to the reabsorption of fluid and electrolytes in these segments. The contribution of NHE3 to fluid reabsorption was assessed by micropuncture in homozygous ( Nhe3 −/−) and heterozygous ( Nhe3 +/−) knockout mice, and in their wild-type (WT, Nhe3 +/+) littermates. Arterial pressure was lower in the Nhe3 −/−mice (89 ± 6 mmHg) compared with Nhe3 +/+ (118 ± 4) and Nhe3 +/−(108 ± 5). Collections from proximal and distal tubules demonstrated that proximal fluid reabsorption was blunted in both Nhe3 +/− and Nhe3 −/−mice (WT, 4.2 ± 0.3; Nhe3 +/−, 3.4 ± 0.2; and Nhe3 −/−, 2.6 ± 0.3 nl/min; P < 0.05). However, distal delivery of fluid was not different among the three groups of mice (WT, 3.3 ± 0.4 nl/min; Nhe3 +/−, 3.3 ± 0.2 nl/min; and Nhe3 −/−, 3.0 ± 0.4 nl/min; P < 0.05). In Nhe3 −/−mice, this compensation was largely attributable to decreased single-nephron glomerular filtration rate (SNGFR): 10.7 ± 0.9 nl/min in the Nhe3 +/+ vs. 6.6 ± 0.8 nl/min in the Nhe3 −/−, measured distally. Proximal-distal SNGFR differences in Nhe3 −/−mice indicated that much of the decrease in SNGFR was due to activation of tubuloglomerular feedback (TGF), and measurements of stop-flow pressure confirmed that TGF is intact in Nhe3 −/−animals. In contrast to Nhe3 −/−mice, normalization of early distal flow rate in Nhe3 +/−mice was not related to decreased SNGFR (9.9 ± 0.7 nl/min), but rather, to increased fluid reabsorption in the loop segment ( Nhe3 +/+, 2.6 ± 0.2; Nhe3 +/−, 3.6 ± 0.5 nl/min). We conclude that NHE3 is a major Na/H exchanger isoform mediating Na+ and fluid reabsorption in the proximal tubule. In animals with NHE3 deficiency, normalization of fluid delivery to the distal tubule is achieved through alterations in filtration rate and/or downstream transport processes.

Depolarization of the macula densa induces superoxide production via NAD(P)H oxidase

2007 ◽  
Vol 292 (6) ◽  
pp. F1867-F1872 ◽  
Author(s):  
Ruisheng Liu ◽  
Jeffrey L. Garvin ◽  
YiLin Ren ◽  
Patrick J. Pagano ◽  
Oscar A. Carretero
Keyword(s):  
Nitric Oxide ◽  
Superoxide Dismutase ◽  
Oxidase Inhibitor ◽  
Fluorescent Dye ◽  
Macula Densa ◽  
Superoxide Production ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Loop Of Henle ◽  
Nacl Concentration

Superoxide (O2−) enhances tubuloglomerular feedback by scavenging nitric oxide at the macula densa. However, the singling pathway of O2− production in the macula densa is not known. We hypothesized that the increase in tubular NaCl concentration that initiates tubuloglomerular feedback induces O2− production by the macula densa via NAD(P)H oxidase, which is activated by macula densa depolarization. We isolated and microperfused the thick ascending limb of the loop of Henle and attached macula densa in rabbits. A fluorescent dye, dihydroethidium, was used to detect O2− production at the macula densa. When luminal NaCl was switched from 10 to 80 mM, a situation of initiating maximum tubuloglomerular feedback response, O2− production significantly increased. To make sure that the shifts in the oxyethidium/dihydroethidium ratio were due to changes in O2−, we used tempol (10−4 M), a stable membrane-permeant superoxide dismutase mimetic. With tempol present, when we switched from 10 to 80 mM NaCl, the increase in oxyethidium/dihydroethidium ratio was blocked. To determine the source of O2−, we used the NAD(P)H oxidase inhibitor apocynin. When luminal NaCl was switched from 10 to 80 mM in the presence of apocynin, O2− production was inhibited by 80%. To see whether the effect of increasing luminal NaCl involves Na-K-2Cl cotransporters, we inhibited them with furosemide. When luminal NaCl was switched from 10 to 80 mM in the presence of furosemide, O2− production was blocked. To test whether depolarization of the macula densa induces O2− production, we artificially induced depolarization by adding valinomycin (10−6 M) and 25 mM KCl to the luminal perfusate. Depolarization alone significantly increases O2− production. We conclude that increasing luminal NaCl induces O2− production during tubuloglomerular feedback. O2− generated by the macula densa is primarily derived from NAD(P)H oxidase and is induced by depolarization.

scholarly journals Effects of NKCC2 isoform regulation on NaCl transport in thick ascending limb and macula densa: a modeling study

2014 ◽  
Vol 307 (2) ◽  
pp. F137-F146 ◽  
Author(s):  
Aurélie Edwards ◽  
Hayo Castrop ◽  
Kamel Laghmani ◽  
Volker Vallon ◽  
Anita T. Layton
Keyword(s):  
Cell Model ◽  
Basolateral Membrane ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Differential Splicing ◽  
Dietary Salt ◽  
Nacl Transport ◽  
Low Salt

This study aims to understand the extent to which modulation of the Na+-K+-2Cl− cotransporter NKCC2 differential splicing affects NaCl delivery to the macula densa. NaCl absorption by the thick ascending limb and macula densa cells is mediated by apical NKCC2. A recent study has indicated that differential splicing of NKCC2 is modulated by dietary salt (Schieβl IM, Rosenauer A, Kattler V, Minuth WW, Oppermann M, Castrop H. Am J Physiol Renal Physiol 305: F1139–F1148, 2013). Given the markedly different ion affinities of its splice variants, modulation of NKCC2 differential splicing is believed to impact NaCl reabsorption. To assess the validity of that hypothesis, we have developed a mathematical model of macula densa cell transport and incorporated that cell model into a previously applied model of the thick ascending limb (Weinstein AM, Krahn TA. Am J Physiol Renal Physiol 298: F525–F542, 2010). The macula densa model predicts a 27.4- and 13.1-mV depolarization of the basolateral membrane [as a surrogate for activation of tubuloglomerular feedback (TGF)] when luminal NaCl concentration is increased from 25 to 145 mM or luminal K+ concentration is increased from 1.5 to 3.5 mM, respectively, consistent with experimental measurements. Simulations indicate that with luminal solute concentrations consistent with in vivo conditions near the macula densa, NKCC2 operates near its equilibrium state. Results also suggest that modulation of NKCC2 differential splicing by low salt, which induces a shift from NKCC2-A to NKCC2-B primarily in the cortical thick ascending limb and macula densa cells, significantly enhances salt reabsorption in the thick limb and reduces Na+ and Cl− delivery to the macula densa by 3.7 and 12.5%, respectively. Simulation results also predict that the NKCC2 isoform shift hyperpolarizes the macula densa basolateral cell membrane, which, taken in isolation, may inhibit the release of the TGF signal. However, excessive early distal salt delivery and renal salt loss during a low-salt diet may be prevented by an asymmetric TGF response, which may be more sensitive to flow increases.

Regulation by glucocorticoids and osmolality of expression of ROMK (Kir 1.1), the apical K channel of thick ascending limb

2003 ◽  
Vol 284 (5) ◽  
pp. F977-F986 ◽  
Author(s):  
Morgan Gallazzini ◽  
Amel Attmane-Elakeb ◽  
David B. Mount ◽  
Steven C. Hebert ◽  
Maurice Bichara
Keyword(s):  
Protein Expression ◽  
In Vivo Studies ◽  
K Channel ◽  
Thick Ascending Limb ◽  
Rt Pcr ◽  
Immunoblotting Analysis ◽  
Medullary Thick Ascending Limb ◽  
Nacl Concentration ◽  
Mrna And Protein Expression

Mechanisms of regulation of ROMK channel mRNA and protein expression in medullary thick ascending limb (MTAL) were assessed in rat MTAL fragments incubated for 7 h. ROMK mRNA was quantified by quantitative RT-PCR and ROMK protein by immunoblotting analysis of crude membranes. Medium hyperosmolality (450 mosmol/kgH2O; NaCl plus urea added to isoosmotic medium) increased ROMK mRNA ( P < 0.04) and protein ( P < 0.006), and 10 nM dexamethasone also increased ROMK mRNA ( P < 0.02). Hyperosmolality and dexamethasone had no additive effects on ROMK mRNA. NaCl alone, but not urea or mannitol, reproduced the hyperosmolality effect on ROMK mRNA. 1-Deamino-(8-d-arginine) vasopressin (1 nM) or 0.5 mM 8-bromo-cAMP had no effect per se on ROMK mRNA and protein. However, 8-bromo-cAMP abolished the stimulatory effect of dexamethasone on ROMK mRNA in the isoosmotic but not in the hyperosmotic medium ( P < 0.004). In in vivo studies, the abundance of ROMK protein and mRNA increased in adrenalectomized (ADX) rats infused with dexamethasone compared with ADX rats ( P < 0.02). These results establish glucocorticoids and medium NaCl concentration as direct regulators of MTAL ROMK mRNA and protein expression, which may be modulated by cAMP-dependent factors.

scholarly journals Connecting tubule glomerular feedback antagonizes tubuloglomerular feedback in vivo

2010 ◽  
Vol 299 (6) ◽  
pp. F1374-F1378 ◽  
Author(s):  
H. Wang ◽  
J. L. Garvin ◽  
M. A. D'Ambrosio ◽  
Y. Ren ◽  
O. A. Carretero
Keyword(s):  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
In Vitro Experiments ◽  
Nacl Transport ◽  
Connecting Tubule ◽  
Vasoconstrictor Effect ◽  
Flow Pressure ◽  
Stop Flow

In vitro experiments showed that the connecting tubule (CNT) sends a signal that dilates the afferent arteriole (Af-Art) when Na+ reabsorption in the CNT lumen increases. We call this process CNT glomerular feedback (CTGF) to differentiate it from tubuloglomerular feedback (TGF), which is a cross talk between the macula densa (MD) and the Af-Art. In TGF, the MD signals the Af-Art to constrict when NaCl transport by the MD is enhanced by increased luminal NaCl. CTGF is mediated by CNT Na+ transport via epithelial Na+ channels (ENaC). However, we do not know whether CTGF occurs in vivo or whether it opposes the increase in Af-Art resistance caused by TGF. We hypothesized that CTGF occurs in vivo and opposes TGF. To test our hypothesis, we conducted in vivo micropuncture of individual rat nephrons, measuring stop-flow pressure (PSF) as an index of glomerular filtration pressure. To test whether activation of CTGF opposes TGF, we used benzamil to block CNT Na+ transport and thus CTGF. CTGF inhibition with the ENaC blocker benzamil (1 μM) potentiated the decrease in PSF at 40 and 80 nl/min. Next, we tested whether we could augment CTGF by inhibiting NaCl reabsorption in the distal convoluted tubule with hydrochlorothiazide (HCTZ, 1 mM) to enhance NaCl delivery to the CNT. In the presence of HCTZ, benzamil potentiated the decrease in PSF at 20, 40, and 80 nl/min. We concluded that in vivo CTGF occurs and opposes the vasoconstrictor effect of TGF.

scholarly journals Role of connecting tubule glomerular feedback in obesity related renal damage

2018 ◽  
Vol 315 (6) ◽  
pp. F1708-F1713 ◽  
Author(s):  
Sumit R. Monu ◽  
Mani Maheshwari ◽  
Edward L. Peterson ◽  
Oscar A. Carretero
Keyword(s):  
Sodium Channel ◽  
Renal Damage ◽  
Epithelial Sodium Channel ◽  
Indirect Measurement ◽  
Tubuloglomerular Feedback ◽  
Nacl Transport ◽  
Connecting Tubule ◽  
Renal Micropuncture ◽  
Flow Pressure

Zucker obese rats (ZOR) have higher glomerular capillary pressure (PGC) that can cause renal damage. PGC is controlled by afferent (Af-Art) and efferent arteriole (Ef-Art) resistance. Af-Art resistance is regulated by factors that regulate other arterioles, such as myogenic response. In addition, it is also regulated by 2 intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that increased CTGF contributes to TGF attenuation, which in turn increases PGC in ZOR. We performed a renal micropuncture experiment and measured stop-flow pressure (PSF), which is an indirect measurement of PGC in ZOR. Maximal TGF response at 40 nl/min was attenuated in ZOR (4.47 ± 0.60 mmHg) in comparison to the Zucker lean rats (ZLR; 8.54 ± 0.73 mmHg, P < 0.05), and CTGF was elevated in ZOR (5.34 ± 0.87 mmHg) compared with ZLR (1.12 ± 1.28 mmHg, P < 0.05). CTGF inhibition with epithelial sodium channel blocker normalized the maximum PSF change in ZOR indicating that CTGF plays a significant role in TGF attenuation (ZOR, 10.67 ± 1.07 mmHg vs. ZLR, 9.5 ± 1.53 mmHg). We conclude that enhanced CTGF contributes to TGF attenuation in ZOR and potentially contribute to progressive renal damage.

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