Connecting tubule glomerular feedback antagonizes tubuloglomerular feedback in vivo

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.

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Abstract 490: Constrictor Mechanism of the Afferent Arteriole Initiated by Na/H Exchanger in the Nephron

Hypertension ◽

10.1161/hyp.60.suppl_1.a490 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Hong Wang ◽

Martin A D'Ambrosio ◽

YiLin Ren ◽

Jeffrey L Garvin ◽

Oscar A Carretero

Keyword(s):

Macula Densa ◽

Tubuloglomerular Feedback ◽

Na Channel ◽

Afferent Arteriole ◽

Renal Vasculature ◽

Connecting Tubule ◽

Flow Pressure ◽

Stop Flow ◽

Epithelial Na Channel

The afferent arteriole (Af-Art) accounts for most of renal vasculature resistance, thus controlling glomerular filtration rate and renal function. Two mechanisms have been described in which the nephron helps control Af-Art resistance, namely tubuloglomerular feedback (TGF), and connecting tubule glomerular feedback (CTGF). TGF is a constrictor mechanism initiated at the macula densa by the Na/K/2Cl cotransporter (NKCC2), while CTGF is a dilator mechanism initiated at the connecting tubule by the epithelial Na channel (ENaC). However, when NKCC2 is blocked by furosemide, CTGF-induced Af-Art dilation is not evident, thus we hypothesize that there is a constrictor mechanism that is furosemide-insensitive and counters CTGF. To test this, we used in vivo micropuncture of single nephrons. Stop-flow pressure (P SF ) was measured as an index of glomerular capillary pressure (which decreases when the Af-Art constricts). Two consecutive P SF curves were generated by raising nephron perfusion from 0 to 40 nL/min while adding drugs to the tubular perfusate. The decrease in P SF induced by increasing nephron perfusion was blocked by furosemide 10 -4 M (control: 7.9±0.2 mmHg, furosemide: 0.4±0.2 mmHg, P <0.001, n=6), but was partially restored when blocking CTGF with the ENaC inhibitor benzamil 10 -6 M (furosemide: 0.2±0.1 mmHg, furosemide+benzamil: 4.3±0.3 mmHg, P <0.001, n=6). A possible explanation for these observations is that TGF may be activated to some degree by Na/H exchanger (NHE)-mediated Na entry at the macula densa when NKCC2 is blocked. When we added the NHE blocker dimethylamiloride (DMA, 10 -4 M) in the presence of furosemide and benzamil, the decrease in PSF was significantly prevented (furosemide+benzamil: 4.6±0.3 mmHg, furosemide+benzamil+DMA: 1.1±0.2 mmHg, P <0.001, n=6). Therefore, we conclude that a constrictor mechanism of the Af-Art is initiated by NHE in the nephron and is observable when NKCC2-mediated TGF and ENaC-mediated CTGF have been blocked.

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Abstract 066: Regulation of Nephron Afferent Arteriole Resistance in Obesity: Role of Insulin and Connecting Tubule Glomerular Feedback

Hypertension ◽

10.1161/hyp.70.suppl_1.066 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Sumit R Monu ◽

Yilin Ren ◽

Mani Maheshwari ◽

Ed Peterson ◽

Oscar A Carretero

Keyword(s):

Renal Damage ◽

Maximal Response ◽

Nacl Transport ◽

Connecting Tubule ◽

Renal Micropuncture ◽

Flow Pressure ◽

Epithelial Sodium Channel Enac

Introduction: In obesity, increased glomerular capillary pressure (P GC ) may participate in renal damage.P GC is controlled in part by afferent arteriolar ( Af-Art ) resistance that in turn is regulated by two renal intrinsic feedback mechanisms, the vasoconstrictor Tubulo-Glomerular Feedback (TGF), and vasodilator Connecting Tubule Glomerular Feedback (CTGF). CTGF is initiated by an increase in NaCl transport by the epithelial sodium channel (ENaC) in the connecting tubule (CNT). Interestingly, obesity is strongly associated with hyperinsulinemia and insulin is a potent ENaC activator. Hypothesis: In obesity, hyperinsulinemia increases CTGF via activation of the ENaC, this increase, in turn, contributes to TGF attenuation leading to increased P GC and renal damage. Methods: In vivo : In zucker obese rats (ZOR) and zucker lean rats (ZLR), we measured TGF and CTGF using renal micropuncture at 9-10 weeks of age. We quantify stop-flow pressure (P SF ) as an index of P GC . We measured proteinuria as a marker of renal damage in both ZOR and ZLR. In vitro: Microdissected rabbit Af-Arts and their adherent CNTs were perfused with NaCl, insulin or ENaC inhibitor (Benzamil; BZ) to investigate the role of insulin on TGF and CTGF. Results: In-vivo : Maximal TGF response was significantly less in ZOR (6.11 ± 0.75 mmHg) in comparison to the ZLR (9.5 ± 1.1 mmHg, p<0.05). CTGF inhibition by BZ normalized the TGF response in ZOR similar to ZLR (ZOR, 14.01±1.70 mmHg vs ZLR, 11.46± 2.25 mmHg) suggesting CTGF playing a key role in TGF resetting in ZOR. Additionally, ZOR develops proteinuria (mg/24h) at 12 weeks of age (ZOR; 24.85±3.02 vs ZLR; 7.21±1.09, p<0.05 ). In-vitro microperfusion of NaCl in the CNT that elicited a half-maximal response (EC 50 , mmol/L) of Af-Art dilation was 25.0±0.8; an addition of insulin 10 -7 mol/l to the CNT lumen decreased the EC 50 to 8.1±0.8 ( P <0.05) suggesting insulin potentiates CTGF. BZ blocked the insulin-mediated CTGF (Insulin EC 50 : 7.8±0.9 vs . Insulin+BZ, EC 50 : 19.7±5.5; P <0.05). Conclusion: In-vivo : TGF is reset in ZOR due to enhanced CTGF before they develop proteinuria. In-vitro : Insulin increased CTGF during microperfusion experiments. Perspective: Insulin-induced increased in CTGF may explain higher P GC and renal damage in obesity.

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Abstract P325: Enhanced Afferent Arteriole Dilatation in Dahl Salt-sensitive Rats (dahlss): Role of Connecting Tubule Glomerular Feedback (ctgf)

Hypertension ◽

10.1161/hyp.68.suppl_1.p325 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Hong Wang ◽

Cesar A Romero ◽

Branislava Janic ◽

Edwards Peterson ◽

Oscar A Carretero

Keyword(s):

Indirect Measurement ◽

Tubuloglomerular Feedback ◽

Afferent Arteriole ◽

High Salt Diet ◽

Connecting Tubule ◽

Simultaneous Inhibition ◽

Flow Pressure ◽

Tubular Flow

Afferent arteriole (Af-Art) resistance is modulated by 2 intrinsic nephron feedbacks: the vasoconstrictor tubuloglomerular feedback (TGF) and the vasodilator CTGF. TGF is mediated by NKCC2 channel in the macula densa and blocked by furosemide; and CTGF is mediated by ENaC in the connecting tubule and blocked by benzamil. Previously we measured CTGF indirectly, by differences between TGF response with and without CTGF blocker benzamil. Thus, using this indirect measurement we reported that Dahl SS have greater CTGF than Dahl salt-resistant rats (Dahl SR). We have recently developed a new method to measure CTGF more directly and we found that when we simultaneously blocked TGF with furosemide and CTGF with benzamil, the increasing tubular perfusion caused Af-Art constriction (TGF-like) that is mediated by the NHE. W e hypothesize that in vivo during simultaneous inhibition of NKCC2 and the NHE, CTGF causes an Af-Art dilatation revealed by an increase in stop-flow pressure (P SF ) and that is greater in Dahl SS than in Dahl SR in a high salt diet. In the presence of furosemide alone, increasing nephron perfusion did not change the P SF in neither Dahl SS nor Dahl SR. When we blocked both, NKCC2 with furosemide and NHE with DMA, increase in tubular flow caused Af-Art dilation that was demonstrated by an increase in P SF . This increase was greater in Dahl SS (5.1±0.4 mmHg) than in Dahl SR (2.9±0.3 mmHg; P < 0.01), (Fig).We confirm that CTGF causes this vasodilation, since benzamil completely blocked this effect. We conclude that during inhibition of NKCC2 and NHE in the nephron CTGF (Af-Art dilatation) is enhanced in Dahl SS as compared to Dahl SR.

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Connecting tubule glomerular feedback mediates acute tubuloglomerular feedback resetting

AJP Renal Physiology ◽

10.1152/ajprenal.00673.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. F1300-F1304 ◽

Cited By ~ 16

Author(s):

Hong Wang ◽

Martin A. D'Ambrosio ◽

Jeffrey L. Garvin ◽

Yilin Ren ◽

Oscar A. Carretero

Keyword(s):

Carbonic Anhydrase ◽

Proximal Tubule ◽

Sodium Channels ◽

Tubuloglomerular Feedback ◽

Afferent Arteriole ◽

Epithelial Sodium Channels ◽

Connecting Tubule ◽

Before And After ◽

Flow Pressure ◽

Stop Flow

Tubuloglomerular feedback (TGF) and connecting tubule glomerular feedback (CTGF) are mechanisms that control afferent arteriole (Af-Art) tone. TGF, initiated by increased NaCl at the macula densa, causes Af-Art constriction. Prolonged activation of TGF leads to an attenuation or “resetting” of its constrictor effect. The mechanisms of TGF resetting remain incompletely understood. CTGF is initiated by increased NaCl in the connecting tubule and Na+ entry via epithelial sodium channels (ENaC). Contrary to TGF, CTGF dilates the Af-Art. Here, we hypothesize that CTGF, in part, mediates TGF resetting. We performed micropuncture of individual rat nephrons while measuring stop-flow pressure (PSF), an index of glomerular filtration pressure and Af-Art tone. Increases in Af-Art tone cause PSF to decrease. TGF responses, measured as the decrease in PSF induced by switching late proximal tubule perfusion from 5 to 40 nl/min, were elicited before and after a 30-min period of sustained perfusion of the late proximal tubule at a rate of 40 nl/min designed to induce TGF resetting. TGF responses were 7.3 ± 0.3 and 4.9 ± 0.2 mmHg before and after resetting was induced ( P < 0.001, n = 6). When CTGF was inhibited with the ENaC blocker benzamil (1 μM), TGF responses were 9.5 ± 0.3 and 8.8 ± 0.6 mmHg (NS, n = 6), thus resetting was abolished. In the presence of the carbonic anhydrase inhibitor acetazolamide (10 mM), TGF responses were 8.8 ± 0.6 and 3.3 ± 0.4 mmHg before and after resetting ( P < 0.001, n = 6). With both acetazolamide and benzamil, TGF responses were 10.4 ± 0.2 and 8.4 ± 0.5 mmHg ( P < 0.01, n = 6), thus resetting was attenuated. We conclude that CTGF, in part, mediates acutely induced TGF resetting.

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Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron

AJP Renal Physiology ◽

10.1152/ajprenal.00605.2014 ◽

2015 ◽

Vol 308 (9) ◽

pp. F1026-F1031 ◽

Cited By ~ 11

Author(s):

Hong Wang ◽

Martin A. D'Ambrosio ◽

YiLin Ren ◽

Sumit R. Monu ◽

Pablo Leung ◽

...

Keyword(s):

Capillary Pressure ◽

Tubuloglomerular Feedback ◽

Na Channels ◽

Epithelial Na Channels ◽

Transport Inhibitors ◽

Flow Pressure ◽

Tubular Flow ◽

Stop Flow

Afferent (Af-Art) and efferent arterioles resistance regulate glomerular capillary pressure. The nephron regulates Af-Art resistance via: 1) vasoconstrictor tubuloglomerular feedback (TGF), initiated in the macula densa via Na-K-2Cl cotransporters (NKCC2) and 2) vasodilator connecting tubuloglomerular feedback (CTGF), initiated in connecting tubules via epithelial Na channels (ENaC). Furosemide inhibits NKCC2 and TGF. Benzamil inhibits ENaC and CTGF. In vitro, CTGF dilates preconstricted Af-Arts. In vivo, benzamil decreases stop-flow pressure (PSF), suggesting that CTGF antagonizes TGF; however, even when TGF is blocked, CTGF does not increase PSF, suggesting there is another mechanism antagonizing CTGF. We hypothesize that in addition to NKCC2, activation of Na/H exchanger (NHE) antagonizes CTGF, and when both are blocked CTGF dilates Af-Arts and this effect is blocked by a CTGF inhibitor benzamil. Using micropuncture, we studied the effects of transport inhibitors on TGF responses by measuring PSF while increasing nephron perfusion from 0 to 40 nl/min. Control TGF response (−7.9 ± 0.2 mmHg) was blocked by furosemide (−0.4 ± 0.2 mmHg; P < 0.001). Benzamil restored TGF in the presence of furosemide (furosemide: −0.2 ± 0.1 vs. furosemide+benzamil: −4.3 ± 0.3 mmHg; P < 0.001). With furosemide and NHE inhibitor, dimethylamiloride (DMA), increase in tubular flow increased PSF (furosemide+DMA: 2.7 ± 0.5 mmHg, n = 6), and benzamil blocked this (furosemide+DMA+benzamil: −1.1 ± 0.2 mmHg; P < 0.01, n = 6). We conclude that NHE in the nephron decreases PSF (Af-Art constriction) when NKCC2 and ENaC are inhibited, suggesting that in the absence of NKCC2, NHE causes a TGF response and that CTGF dilates the Af-Art when TGF is blocked with NKCC2 and NHE inhibitors.

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Connecting tubule glomerular feedback mediates tubuloglomerular feedback resetting after unilateral nephrectomy

AJP Renal Physiology ◽

10.1152/ajprenal.00619.2016 ◽

2018 ◽

Vol 315 (4) ◽

pp. F806-F811 ◽

Cited By ~ 5

Author(s):

Sumit R. Monu ◽

Yilin Ren ◽

J. X. Masjoan-Juncos ◽

Kristopher Kutskill ◽

Hong Wang ◽

...

Keyword(s):

Indirect Measurement ◽

Tubuloglomerular Feedback ◽

Sprague Dawley ◽

Glomerular Injury ◽

Nacl Transport ◽

Connecting Tubule ◽

Flow Pressure ◽

Stop Flow ◽

Remnant Kidney ◽

Epithelial Sodium Channel Enac

Unilaterally nephrectomized rats (UNx) have higher glomerular capillary pressure (PGC) that can cause significant glomerular injury in the remnant kidney. PGC is controlled by the ratio of afferent (Af-Art) and efferent arteriole resistance. Af-Art resistance in turn is regulated by two 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 (ENaC). Resetting of TGF post-UNx can allow systemic pressure to be transmitted to the glomerulus and cause renal damage, but the mechanism behind this resetting is unclear. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that CTGF is increased after UNx and contributes to TGF resetting. To test this hypothesis, we performed UNx in Sprague-Dawley (8) rats. Twenty-four hours after surgery, we performed micropuncture of individual nephrons and measured stop-flow pressure (PSF). PSF is an indirect measurement of PGC. Maximal TGF response at 40 nl/min was 8.9 ± 1.24 mmHg in sham-UNx rats and 1.39 ± 1.02 mmHg in UNx rats, indicating TGF resetting after UNx. When CTGF was inhibited with the ENaC blocker benzamil (1 μM/l), the TGF response was 12.29 ± 2.01 mmHg in UNx rats and 13.03 ± 1.25 mmHg in sham-UNx rats, indicating restoration of the TGF responses in UNx. We conclude that enhanced CTGF contributes to TGF resetting after UNx.

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Abstract 062: Regulation of Nephron Afferent Arteriole Resistance in Obesity: Role of Connecting Tubule Glomerular Feedback

Hypertension ◽

10.1161/hyp.68.suppl_1.062 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Sumit R Monu ◽

Mani Maheshwari ◽

Hong Wang ◽

Ed Peterson ◽

Oscar Carretero

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Tubuloglomerular Feedback ◽

Afferent Arteriole ◽

Connecting Tubule ◽

Single Nephron ◽

Renal Micropuncture ◽

The Difference

In obesity, renal damage is caused by increase in renal blood flow (RBF), glomerular capillary pressure (P GC ), and single nephron glomerular filtration rate but the mechanism behind this alteration in renal hemodynamics is unclear. P GC is controlled mainly by the afferent arteriole (Af-Art) resistance. Af-Art resistance is regulated by mechanism similar to that in other arterioles and in addition, it is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to an increase in sodium chloride (NaCl) in the macula densa, via sodium–potassium-2-chloride cotransporter-2 (NKCC2) and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation and is mediated by connecting tubule via epithelial sodium channel (ENaC). CTGF is blocked by the ENaC inhibitor benzamil. Attenuation of TGF reduces Af-Art resistance and allows systemic pressure to get transmitted to the glomerulus that causes glomerular barotrauma/damage. In the current study, we tested the hypothesis that TGF is attenuated in obesity and that CTGF contributes to this effect. We used Zucker obese rats (ZOR) while Zucker lean rats (ZLR) served as controls. We performed in-vivo renal micropuncture of individual rat nephrons while measuring stop-flow pressure (P SF ), an index of P GC. TGF response was measured as a decrease in P SF induced by changing the rate of late proximal perfusion from 0 to 40nl/min in stepwise manner.CTGF was calculated as the difference of P SF value between vehicle and benzamil treatment, at each perfusion rate. Maximal TGF response was significantly less in ZOR (6.16 ± 0.52 mmHg) when compared to the ZLR (8.35 ± 1.00mmHg), p<0.05 , indicating TGF resetting in the ZOR. CTGF was significantly higher in ZOR (6.33±1.95 mmHg) when compared to ZLR (1.38±0.89 mmHg), p<0.05 . When CTGF was inhibited with the ENaC blocker Benzamil (1μM), maximum P SF decrease was 12.30±1.72 mmHg in ZOR and 10.60 ± 1.73 mmHg in ZLR, indicating that blockade of CTGF restored TGF response in ZOR. These observations led us to conclude that TGF is reset in ZOR and that enhanced CTGF contributes to this effect. Increase in CTGF may explain higher renal blood flow, increased P GC and higher glomerular damage in obesity.

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Native tubular fluid attenuates ANF-induced inhibition of tubuloglomerular feedback

AJP Renal Physiology ◽

10.1152/ajprenal.1990.258.1.f189 ◽

1990 ◽

Vol 258 (1) ◽

pp. F189-F198 ◽

Cited By ~ 5

Author(s):

D. M. Pollock ◽

W. J. Arendshorst

Keyword(s):

Atrial Natriuretic Factor ◽

Filtration Rate ◽

Pressure Range ◽

Tubuloglomerular Feedback ◽

Fluid Delivery ◽

Single Nephron ◽

Proximal Tubular ◽

Flow Pressure ◽

Stop Flow

The effect of atrial natriuretic factor [ANF-(1–28); 0.25 microgram.kg-1.min-1] on tubuloglomerular feedback (TGF) and the efficiency of renal blood flow (RBF) autoregulation was determined in anesthetized euvolemic rats. In microperfusion studies, ANF dramatically inhibited (greater than 80%) feedback-mediated decreases in single-nephron glomerular filtration rate (SNGFR) and stop-flow pressure (Psf) when Henle's loop was perfused at 0–48 nl/min with artificial fluid. The sigmoidal relationship between Psf and loop perfusion during control was shifted to a linear relation during ANF; reactivity was almost nonexistent and no inflection point could be discerned. ANF almost completely blocked maximum Psf and SNGFR responses to loop perfusion at rates greater than 24 nl/min. In contrast 30 nl/min loop perfusion with native proximal tubular fluid obtained during ANF infusion restored maximum TGF activity to 70% of control levels. During ANF administration, the paired Psf responses to native and artificial perfusate were significantly different (-5.3 vs. -0.8 mmHg, P less than 0.001), compared with similar responses during control conditions (-7.6 vs. -8.3 mmHg, P greater than 0.1). In free-flow studies, ANF increased proximally and distally measured SNGFR equally. The constancy of the proximal-distal SNGFR difference (10.3 vs. 9.3 nl/min) in the presence of increased distal fluid delivery suggests partial inhibition of TGF during ANF administration. ANF elevated Psf but did not affect basal RBF or the RBF autoregulatory index over an arterial pressure range of 130–70 mmHg. These results indicate that 1) RBF autoregulation is efficiently maintained during ANF infusion when preglomerular vessels are vasodilated and TGF is inhibited by approximately 30%; 2) an endogenous factor(s) in native proximal tubular fluid may attenuate ANF-induced inhibition of TGF; and 3) microperfusion studies using artificial fluid significantly overestimate the net in vivo effect of ANF on TGF.

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Modulation of tubuloglomerular feedback responsiveness by extracellular ATP

AJP Renal Physiology ◽

10.1152/ajprenal.1993.264.3.f458 ◽

1993 ◽

Vol 264 (3) ◽

pp. F458-F466 ◽

Cited By ~ 35

Author(s):

K. D. Mitchell ◽

L. G. Navar

Keyword(s):

Saline Solution ◽

Isotonic Saline ◽

Tubuloglomerular Feedback ◽

Peritubular Capillary ◽

Arterial Blood ◽

Transient Decrease ◽

Peritubular Capillaries ◽

Flow Pressure ◽

Stop Flow

Experiments were performed in pentobarbital sodium-anesthetized rats to determine the effects of activation of P2 purinoceptors sensitive to ATP on glomerular capillary pressure, as estimated from proximal tubule stop-flow pressure (SFP) measurements, and on the magnitude of maximal tubuloglomerular feedback-mediated reductions in SFP. To selectively expose nephrons in vivo to ATP without influencing arterial blood pressure, we infused ATP directly into the surrounding peritubular capillaries. Peritubular capillary infusion, at a rate of 20 nl/min, of an isotonic saline solution containing 10(-3) M ATP elicited a transient decrease in resting SFP. However, subsequent infusion of 10(-3) M ATP together with the adenosine receptor (P1 purinoceptor) antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (PSPX, 10(-3) M) into the same vascular sites elicited a sustained decrease in resting SFP. Peritubular infusion of the slowly metabolizable ATP analogue, beta,gamma-methylene-ATP (10(-3) M), at a rate of 20 nl/min, also elicited a transient decrease in SFP, but this was not converted to a sustained response by PSPX. The SFP feedback responses to a late proximal perfusion rate of 40 nl/min were markedly attenuated during peritubular infusion of either 10(-3) M ATP (8.7 +/- 1.2 vs. 1.8 +/- 0.9 mmHg; P < 0.01, n = 9) or 10(-3) M beta,gamma-methylene-ATP (8.2 +/- 1.3 vs. 2.2 +/- 1.2 mmHg; P < 0.01, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

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Effect of salt intake on afferent arteriolar dilatation: role of connecting tubule glomerular feedback (CTGF)

AJP Renal Physiology ◽

10.1152/ajprenal.00320.2017 ◽

2017 ◽

Vol 313 (6) ◽

pp. F1209-F1215 ◽

Cited By ~ 2

Author(s):

Hong Wang ◽

Cesar A. Romero ◽

J. X. Masjoan Juncos ◽

Sumit R. Monu ◽

Edward L. Peterson ◽

...

Keyword(s):

Salt Intake ◽

High Salt ◽

Tubuloglomerular Feedback ◽

Connecting Tubule ◽

High Salt Intake ◽

Simultaneous Inhibition ◽

Flow Pressure ◽

Tubular Flow

Afferent arteriole (Af-Art) resistance is modulated by two intrinsic nephron feedbacks: 1) the vasoconstrictor tubuloglomerular feedback (TGF) mediated by Na+-K+-2Cl− cotransporters (NKCC2) in the macula densa and blocked by furosemide and 2) the vasodilator connecting tubule glomerular feedback (CTGF), mediated by epithelial Na+ channels (ENaC) in the connecting tubule and blocked by benzamil. High salt intake reduces Af-Art vasoconstrictor ability in Dahl salt-sensitive rats (Dahl SS). Previously, we measured CTGF indirectly, by differences between TGF responses with and without CTGF inhibition. We recently developed a new method to measure CTGF more directly by simultaneously inhibiting NKCC2 and the Na+/H+ exchanger (NHE). We hypothesize that in vivo during simultaneous inhibition of NKCC2 and NHE, CTGF causes an Af-Art dilatation revealed by an increase in stop-flow pressure (PSF) in Dahl SS and that is enhanced with a high salt intake. In the presence of furosemide alone, increasing nephron perfusion did not change the PSF in either Dahl salt-resistant rats (Dahl SR) or Dahl SS. When furosemide and an NHE inhibitor, dimethylamiloride, were perfused simultaneously, an increase in tubular flow caused Af-Art dilatation that was demonstrated by an increase in PSF. This increase was greater in Dahl SS [4.5 ± 0.4 (SE) mmHg] than in Dahl SR (2.5 ± 0.3 mmHg; P < 0.01). We confirmed that CTGF causes this vasodilation, since benzamil completely blocked this effect. However, a high salt intake did not augment the Af-Art dilatation. We conclude that during simultaneous inhibition of NKCC2 and NHE in the nephron, CTGF induces Af-Art dilatation and a high salt intake failed to enhance this effect.

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