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.

Abstract P148: Connecting Tubule-glomerular Feedback (ctgf) in Renal Hemodynamics and Blood Pressure (bp) After Unilateral Nephrectomy (unx)

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Cesar A Romero ◽  
Sumit Monu ◽  
Robert Knight ◽  
Oscar A Carretero
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Tubuloglomerular Feedback ◽  
Unilateral Nephrectomy ◽  
Afferent Arteriole ◽  
Sprague Dawley ◽  
High Sodium ◽  
Connecting Tubule ◽  
Chronic Infusion

Afferent arteriole resistance is regulated in part by myogenic response, tubuloglomerular feedback (TGF) and connecting tubule-glomerular feedback (CTGF). CTGF dilates afferent arteriole in response to high sodium in connecting tubule (CNT) counteracting and shifting to the right the TGF response (resetting); CTGF increases renal blood flow and glomerular pressure, both favoring glomerular filtration and sodium excretion. CTGF is initiated by epithelial sodium channel (ENaC) in CNT and inhibited by Benzamil. Unilateral nephrectomy (UNx) is accompanied by TGF resetting, increase in renal blood flow (RBF) and single nephron GFR in the remnant kidney, without any changes in systemic BP. We evaluated the effects of CTGF in TGF resetting, RBF and BP after UNx. UNx was performed on Sprague-Dawley rats and 24h later TGF was evaluated in vivo by renal micropuncture techniques by measure stop flow pressure (Psf). CTGF was evaluated by the differences between TGF maximal responses (TGFmax) with or without tubular benzamil perfusion. Another set of animals received chronic infusion of benzamil directly into the kidney, that started 1 week before UNx. Renal blood flow (RBF) was measured by arterial spin labeling-MRI 24h before and 24h after the UNx. Direct BP measurement was performed before and 3 weeks after the UNx. After UNx, TGF resetting was observed in UNx rats (TGFmax 8±1 vs. 1±1 mmHg, Sham vs. UNx; p<0.05). This TGF resetting was inhibited by benzamil. RBF increased after the UNx in comparison to sham and this increase was prevented by chronic infusion of Benzamil into the kidney (Sham: 3±0.6; UNx: 4.6±0.3; UNx+Benzamil 3.5±0.6 ml/min/g tissue p<0.002). Basal mean BP values were not different between the vehicle or treated rats before the UNx; however 3 weeks after the UNx, rats receiving benzamil into the kidney showed higher mean BP values than vehicle (88±0.3 vs. 97±4 mmHg, p<0.01). We conclude that CTGF participates in TGF resetting and RBF regulation after UNx, and that could participate in BP regulation after UNx.

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.

A novel mechanism of renal blood flow autoregulation and the autoregulatory role of A1 adenosine receptors in mice

2007 ◽  
Vol 293 (5) ◽  
pp. F1489-F1500 ◽  
Author(s):  
Armin Just ◽  
William J. Arendshorst
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Adenosine Receptors ◽  
Time Course ◽  
Tubuloglomerular Feedback ◽  
The Third ◽  
A1 Adenosine Receptors ◽  
The Impact ◽  
Renal Blood Flow Autoregulation

Autoregulation of renal blood flow (RBF) is mediated by a fast myogenic response (MR; ∼5 s), a slower tubuloglomerular feedback (TGF; ∼25 s), and potentially additional mechanisms. A1 adenosine receptors (A1AR) mediate TGF in superficial nephrons and contribute to overall autoregulation, but the impact on the other autoregulatory mechanisms is unknown. We studied dynamic autoregulatory responses of RBF to rapid step increases of renal artery pressure in mice. MR was estimated from autoregulation within the first 5 s, TGF from that at 5–25 s, and a third mechanism from 25–100 s. Genetic deficiency of A1AR (A1AR−/−) reduced autoregulation at 5–25 s by 50%, indicating a residual fourth mechanism resembling TGF kinetics but independent of A1AR. MR and third mechanism were unaltered in A1AR−/−. Autoregulation in A1AR−/− was faster at 5–25 than at 25–100 s suggesting two separate mechanisms. Furosemide in wild-type mice (WT) eliminated the third mechanism and enhanced MR, indicating TGF-MR interaction. In A1AR−/−, furosemide did not further impair autoregulation at 5–25 s, but eliminated the third mechanism and enhanced MR. The resulting time course was the same as during furosemide in WT, indicating that A1AR do not affect autoregulation during furosemide inhibition of TGF. We conclude that at least one novel mechanism complements MR and TGF in RBF autoregulation, that is slower than MR and TGF and sensitive to furosemide, but not mediated by A1AR. A fourth mechanism with kinetics similar to TGF but independent of A1AR and furosemide might also contribute. A1AR mediate classical TGF but not TGF-MR interaction.

Renal 131I-hippurate clearance overestimates true renal blood flow in the instrumented conscious dog

1996 ◽  
Vol 271 (2) ◽  
pp. F269-F274 ◽  
Author(s):  
C. A. Visscher ◽  
D. De Zeeuw ◽  
G. Navis ◽  
A. K. Van Zanten ◽  
P. E. De Jong ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Artery Blood Flow ◽  
Venous Outflow ◽  
Flow Probe ◽  
The Difference ◽  
Probe Calibration ◽  
Clearance Technique ◽  
Venous Plasma

We evaluated renal 131I-hippurate clearance (ERPFhip) as a measure of renal blood flow (RBF) in chronically instrumented conscious dogs. When adjusted for renal hippurate extraction (Ehip, 0.77 +/- 0.01) and hematocrit (Hct, 39.7 +/- 1%), calculated RBFhip (656 +/- 37 ml/min) markedly exceeded renal blood flow measured with renal artery blood flow probes (RBFprobe, 433 +/- 27 ml/min). The discrepancy could not be explained by flow probe calibration, because in vivo comparison of flow probe values with renal venous outflow showed only a slight underestimation of renal blood flow (slope 0.93, 95% confidence interval 0.89-0.97). Redistribution of hippurate from erythrocytes into renal venous plasma during or shortly after blood sampling led to an underestimation of Ehip by 4 +/- 1% and thus could only explain a small part of the difference. Extrarenal hippurate clearance was excluded, because the amount of 131I-hippurate cleared from plasma equaled that appearing in the urine (303 +/- 17 and 307 +/- 17 ml/min). Applying these corrections, we found that RBFhip still exceeded RBFprobe by 37 +/- 3%. These data indicate that renal blood flow measured by the hippurate clearance technique markedly overestimates true renal blood flow. Because other errors were excluded, a combination of sampling of nonrenal blood and intrarenal hippurate extraction from erythrocytes might play a role.

scholarly journals Aging Impairs Renal Autoregulation in Mice

Hypertension ◽  
2020 ◽  
Vol 75 (2) ◽  
pp. 405-412 ◽  
Author(s):  
Jin Wei ◽  
Jinxiu Zhu ◽  
Jie Zhang ◽  
Shan Jiang ◽  
Larry Qu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renal Blood Flow ◽  
Tubuloglomerular Feedback ◽  
Myogenic Response ◽  
Renal Autoregulation ◽  
Integrin Α5 ◽  
Aging Kidney

Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.

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 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 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.

Phospholemman expression in extraglomerular mesangium and afferent arteriole of the juxtaglomerular apparatus

2003 ◽  
Vol 285 (1) ◽  
pp. F121-F129 ◽  
Author(s):  
Randall K. Wetzel ◽  
Kathleen J. Sweadner
Keyword(s):  
Blood Flow ◽  
Membrane Protein ◽  
Molecular Mechanisms ◽  
Juxtaglomerular Apparatus ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Γ Subunit ◽  
Goormaghtigh Cells

The molecular mechanisms with which the juxtaglomerular apparatus accomplishes its twin functions, acute regulation of glomerular blood flow and secretion of renin, are still not clearly understood. Least understood is the role of the extraglomerular mesangial (EM) cells, also known as lacis or Goormaghtigh cells, which lie sandwiched between the macula densa and the afferent and efferent arterioles. Here, we report that immunoreactivity for phospholemman (FXYD1), a single-span membrane protein homologous to the gamma (γ) sub-unit of the Na,K-ATPase, is found in the kidney in EM cells with the Na,K-ATPase β2-subunit and in cortical blood vessels and the afferent arteriole with Na,K-ATPase α2 and β2. Phospholemman's distribution in EM cells is distinct from that of the Na,K-ATPase γ-subunit, which is found on the basolateral surface of macula densa cells with Na,K-ATPase α1 and β1. Phospholemman is a major kinase target, and its location in the juxtaglomerular apparatus suggests that it is involved in tubuloglomerular feedback.

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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