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

Hypertension ◽  
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.

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.

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.

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

Hypertension ◽  
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.

Different role of Schisandrin B on mercury-induced renal damage in vivo and in vitro

Toxicology ◽  
2011 ◽  
Vol 286 (1-3) ◽  
pp. 48-57 ◽  
Author(s):  
Alessandra Stacchiotti ◽  
Giovanni Li Volti ◽  
Antonio Lavazza ◽  
Ilaria Schena ◽  
Maria Francesca Aleo ◽  
...  
Keyword(s):  
Renal Damage ◽  
Schisandrin B

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

Hypertension ◽  
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.

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

2017 ◽  
Vol 313 (6) ◽  
pp. F1209-F1215 ◽  
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.

scholarly journals Connecting tubule glomerular feedback mediates tubuloglomerular feedback resetting after unilateral nephrectomy

2018 ◽  
Vol 315 (4) ◽  
pp. F806-F811 ◽  
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.

In vitro tracheal responses from mice chosen for in vivo lung cholinergic sensitivity

1990 ◽  
Vol 69 (1) ◽  
pp. 274-280 ◽  
Author(s):  
G. G. Weinmann ◽  
C. M. Black ◽  
R. C. Levitt ◽  
C. A. Hirshman
Keyword(s):  
Linear Regression Analysis ◽  
Inbred Strains ◽  
Multiple Linear Regression Analysis ◽  
Maximal Response ◽  
Inbred Strains Of Mice ◽  
Cholinergic Agents ◽  
Cholinergic Sensitivity

We selected two inbred strains of mice based on their different in vivo lung responses to intravenous acetylcholine for studies on the in vitro tracheal responses to contractile and relaxing agents. In addition, we studied the role of cyclooxygenase products on the in vitro responses. Tracheal rings were contracted with increasing concentrations of carbachol and KCl and relaxed with increasing concentrations of isoproterenol after contraction with carbachol at the concentration that produced 30, 50, and 70% of the maximal contraction (EC30, EC50, and EC70, respectively) and KCl at the EC50. Half the tracheae simultaneously underwent the same protocols after pretreatment with indomethacin (3 X 10(-6) M). Despite a severalfold difference in the maximal response to cholinergic agents in vivo, there were no significant differences between the strains in the tracheal responses to carbachol (P = 0.78) or KCl (P = 0.13) in vitro. Both strains showed inhibition of the isoproterenol relaxation by carbachol (P less than 0.0001). Multiple linear regression analysis showed that the strain that was more sensitive to carbachol in vivo was also more sensitive to isoproterenol in vitro after carbachol contraction (P = 0.014). The greater isoproterenol sensitivity of the tracheae from this strain was not present after contraction with KCl, nor were these tracheae more sensitive to relaxation with sodium nitroprusside. Indomethacin pretreatment of the tissues in vitro augmented the maximal response and the sensitivity to carbachol (P less than 0.001) and KCl (P = 0.0006), and this effect was similar in both strains. Evaluation of isoproterenol relaxation after indomethacin pretreatment was confounded by the lower concentrations of carbachol needed for contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Anti-obesity role of Aster glehni extract: in vivo and in vitro effects

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
HM Lee ◽  
TG Ahn ◽  
CW Kim ◽  
HJ An
Keyword(s):  
In Vitro Effects
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