Perturbation analysis of tubuloglomerular feedback in hydropenic and hemorrhaged rats

1983 ◽  
Vol 245 (5) ◽  
pp. F554-F563 ◽  
Author(s):  
L. C. Moore ◽  
J. Mason
Keyword(s):  
Proximal Tubule ◽  
Feedback Loop ◽  
Tubuloglomerular Feedback ◽  
Fluid Delivery ◽  
Intratubular Pressure ◽  
Fluid Load ◽  
Combined Action ◽  
Distal Delivery ◽  
Distal Flow ◽  
Variable Analysis

A closed-feedback-loop method was used to investigate regulation of SNGFR and distal fluid delivery by tubuloglomerular feedback (TGF) in hydropenic and hemorrhaged rats. Unblocked nephrons were perturbed by early proximal perfusion of previously collected, inulin-free, tubular fluid at 0, 7.5, and 15 nl/min, thereby increasing nephron fluid load. The resultant changes in SNGFR, tubular reabsorption, proximal intratubular pressure, and early distal flow were measured. During perfusion, SNGFR decreased and distal flow increased; the effect on reabsorption was variable. Analysis of the data indicated that the combined action of TGF and changes in proximal tubule and Henle's loop reabsorption were able to provide a maximum of 56% compensation for the effect of the perturbation on distal delivery in hydropenic rats and 70% compensation in hemorrhaged rats. In one group of hydropenic rats in which a significant fall in reabsorption was found, the total fluid load presented to the nephron, SNGFR plus the perfusion rate, was significantly better regulated than distal delivery. This result is consistent with the behavior of a model used to estimate the contribution of TGF to the observed regulation. The results indicated that TGF alone could provide 56% compensation for the perturbation in hydropenia and a significantly greater 72% compensation following hemorrhage. The conclusions are 1) that the properties of TGF are sufficient to result in significant regulation of distal fluid delivery and SNGFR, 2) that hemorrhage increases the strength of the TGF response, and 3) that TGF regulation of SNGFR and distal delivery is strongly influenced by changes in proximal tubule and loop of Henle reabsorption.

Tubuloglomerular feedback control of distal fluid delivery: effect of extracellular volume

1986 ◽  
Vol 250 (6) ◽  
pp. F1024-F1032 ◽  
Author(s):  
L. C. Moore ◽  
J. Mason
Keyword(s):  
Feedback Loop ◽  
Extracellular Volume ◽  
Extracellular Fluid ◽  
Tubuloglomerular Feedback ◽  
Response Curves ◽  
Fluid Delivery ◽  
Fluid Load ◽  
Single Nephron ◽  
Distal Delivery ◽  
Distal Flow

A closed-feedback loop micropuncture method was used to examine tubuloglomerular feedback (TGF) and the regulation of distal fluid delivery in hydropenic rats (CON), moderately hemorrhaged rats (HEM), and rats given desoxycorticosterone (DOC) and 0.6% saline to drink. Distal delivery and TGF response curves were measured with four samples per nephron: a spontaneous early distal collection, two distal collections during moderate (7.5 nl/min) and saturating (30 nl/min) perturbations in nephron fluid load, and a proximal collection to measure single-nephron glomerular filtration rate (SNGFR) during TGF inhibition. Arterial pressure, predistal volume reabsorption, SNGFR, and early distal flow were significantly higher in DOC than in HEM; the CON group exhibited intermediate values. Except for a greater maximum TGF response in HEM, the normalized TGF responses were similar in all three groups, as was the regulation of distal fluid delivery. However, the TGF onset threshold and the TGF operating point, defined by the spontaneous rates of early distal flow and SNGFR, were reset such that distal fluid delivery and SNGFR were higher in DOC than in HEM, as was renal sodium excretion. The results show that the level around which TGF stabilizes distal fluid delivery is reset when extracellular fluid volume is altered.

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.

Effect of sustained flow perturbations on stability and compensation of tubuloglomerular feedback

2003 ◽  
Vol 285 (5) ◽  
pp. F972-F989 ◽  
Author(s):  
Darren R. Oldson ◽  
Leon C. Moore ◽  
Harold E. Layton
Keyword(s):  
Mathematical Model ◽  
Proximal Tubule ◽  
Limit Cycle ◽  
Critical Value ◽  
Tubuloglomerular Feedback ◽  
Feedback Gain ◽  
Acta Physiol ◽  
Pressure Oscillations ◽  
Intratubular Pressure ◽  
Abrupt Changes

A mathematical model previously formulated by us predicts that limit-cycle oscillations (LCO) in nephron flow are mediated by tubuloglomerular feedback (TGF) and that the LCO arise from a bifurcation that depends heavily on the feedback gain magnitude, γ, and on its relationship to a theoretically determined critical value of gain, γc. In this study, we used that model to show how sustained perturbations in proximal tubule flow, a common experimental maneuver, can initiate or terminate LCO by changing the values of γ and γc, thus changing the sign of γ - γc. This result may help explain experiments in which intratubular pressure oscillations were initiated by the sustained introduction or removal of fluid from the proximal tubule (Leyssac PP and Baumbach L. Acta Physiol Scand 117: 415–419, 1983). In addition, our model predicts that, for a range of TGF sensitivities, sustained perturbations that initiate or terminate LCO can yield substantial and abrupt changes in both distal NaCl delivery and NaCl delivery compensation, changes that may play an important role in the response to physiological challenge.

scholarly journals Salt sensitivity of tubuloglomerular feedback in the early remnant kidney

2014 ◽  
Vol 306 (2) ◽  
pp. F172-F180 ◽  
Author(s):  
Prabhleen Singh ◽  
Scott C. Thomson
Keyword(s):  
Tubuloglomerular Feedback ◽  
Distal Nephron ◽  
Fluid Delivery ◽  
Sham Surgery ◽  
Single Nephron ◽  
Flow Pressure ◽  
Nacl Excretion ◽  
Stop Flow ◽  
Remnant Kidney ◽  
Distal Delivery

We previously reported internephron heterogeneity in the tubuloglomerular feedback (TGF) response 1 wk after subtotal nephrectomy (STN), with 50% of STN nephrons exhibiting anomalous TGF (Singh P, Deng A, Blantz RC, Thomson SC. Am J Physiol Renal Physiol 296: F1158–F1165, 2009). Presently, we tested the theory that anomalous TGF is an adaptation of the STN kidney to facilitate increased distal delivery when NaCl balance forces the per-nephron NaCl excretion to high levels. To this end, the effect of dietary NaCl on the TGF response was tested by micropuncture in STN and sham-operated Wistar rats. An NaCl-deficient (LS) or high-salt NaCl diet (HS; 1% NaCl in drinking water) was started on day 0 after STN or sham surgery. Micropuncture followed 8 days later with measurements of single-nephron GFR (SNGFR), proximal reabsorption, and tubular stop-flow pressure (PSF) obtained at both extremes of TGF activation, while TGF was manipulated by microperfusing Henle's loop (LOH) from the late proximal tubule. Activating TGF caused SNGFR to decline by similar amounts in Sham-LS, Sham-HS and STN-LS [ΔSNGFR (nl/min) = −16 ± 2, −11 ± 3, −11 ± 2; P = not significant by Tukey]. Activating TGF in STN-HS actually increased SNGFR by 5 ± 2 nl/min ( P < 0.0005 vs. each other group by Tukey). HS had no effect on the PSF response to LOH perfusion in sham [ΔPSF (mmHg) = −9.6 ± 1.1 vs. −9.8 ± 1.0] but eliminated the PSF response in STN (+0.3 ± 0.9 vs. −5.7 ± 1.0, P = 0.0002). An HS diet leads to anomalous TGF in the early remnant kidney, which facilitates NaCl and fluid delivery to the distal nephron.

scholarly journals A mathematical model of the rat nephron: glucose transport

2015 ◽  
Vol 308 (10) ◽  
pp. F1098-F1118 ◽  
Author(s):  
Alan M. Weinstein
Keyword(s):  
Filtration Rate ◽  
Tubuloglomerular Feedback ◽  
Renal Tubules ◽  
Distal Nephron ◽  
Osmotic Diuresis ◽  
Fluid Delivery ◽  
Glucose Reabsorption ◽  
Sglt2 Inhibition ◽  
Model Equations ◽  
Distal Delivery

Mathematical models of the proximal tubule (PT), loop of Henle (LOH), and distal nephron have been combined to simulate transport by rat renal tubules. The ensemble is composed of 24,000 superficial (SF) nephrons and 12,000 juxtamedullary (JM) nephrons in 5 classes (according to LOH length); all coalesce into 7,200 connecting tubules (CNT). Medullary interstitial solute concentrations are specified. The model equations require that each nephron glomerular filtration rate (GFR) satisfies a tubuloglomerular feedback (TGF) relationship, and each initial hydrostatic pressure yields a common CNT pressure; that common CNT pressure is determined from an overall distal hydraulic resistance to flow. By virtue of the greater GFR for JM nephrons, fluid delivery to SF and JM tubules is comparable. Glucose reabsorption is restricted to the PT, cotransported with one Na in the convoluted tubule (SGLT2), and two Na in the straight tubule (SGLT1). Increasing ambient glucose from 5 to 10 mM increases proximal Na reabsorption and decreases distal delivery. This is mitigated by a TGF-mediated increase in GFR, and may thus be an etiology for TGF-mediated glomerular hyperfiltration. With SGLT2 inhibition by 95%, the model predicts that under normoglycemic conditions about 60% of filtered glucose will still be reabsorbed, so that profound glycosuria is not to be expected. Compared with glucose-driven osmotic diuresis, SGLT2 inhibition provokes greater natriuresis. When hyperglycemia is superimposed on SGLT2 inhibition, the model suggests that natriuresis may be severe, reflecting synergy of a proximal diuretic and osmotic diuresis. In sum, the model captures TGF-mediated diabetic hyperfiltration and predicts glomerular protection with SGLT2 inhibition.

Tubuloglomerular feedback responses to acute contralateral nephrectomy

1991 ◽  
Vol 260 (5) ◽  
pp. F749-F756 ◽  
Author(s):  
R. C. Blantz ◽  
O. W. Peterson ◽  
S. C. Thomson
Keyword(s):  
Urinary Excretion ◽  
Proximal Tubule ◽  
Filtration Rate ◽  
Turning Point ◽  
Maximal Activity ◽  
Tubuloglomerular Feedback ◽  
Renal Hypertrophy ◽  
Fitting Procedure ◽  
Single Nephron ◽  
Distal Flow

After unilateral nephrectomy adaptive events must occur in the remaining kidney within the first 12-14 h in anticipation of an increase in glomerular filtration rate (GFR) and eventual renal hypertrophy. Utilizing micropuncture and microperfusion techniques in the rat, we have examined tubuloglomerular feedback (TGF) and single-nephron GFR (SNGFR) responses while the late proximal tubule was microperfused [late proximal tubule flow (VLP)] from 0 to 40 nl/min in 10 nl/min intervals at 2-4 and 12 h after contralateral nephrectomy. Urinary excretion increased, but SNGFR derived from distal collections was reduced, and early distal flow rate remained constant 2-4 h after nephrectomy. The operating point was shifted, suggesting activation of TGF. The turning point half-maximal activity (V1/2) and slope were not statistically different when all nephron data were submitted to a curve-fitting procedure, but group mean data suggested a quantitatively lower V1/2 and steeper slope of the TGF profile. Twelve to fourteen hours after contralateral nephrectomy, values for SNGFR at all microperfusion rates were increased, as were late proximal and early distal flow rates. The values for V1/2 and slope of TGF were not statistically different from control values. We conclude that TGF activity and sensitivity are not suppressed at 2 and 12 h after nephrectomy. Increased urinary excretion does not require TGF alterations. Changes in TGF may be adaptive to increases in SNGFR and may not be causal to the increase in filtration rate after nephrectomy.

Abnormalities in glomerular function in rats developing spontaneous hypertension

1984 ◽  
Vol 246 (1) ◽  
pp. F12-F20 ◽  
Author(s):  
J. R. Dilley ◽  
C. T. Stier ◽  
W. J. Arendshorst
Keyword(s):  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Fluid Collection ◽  
Spontaneously Hypertensive ◽  
Fluid Delivery ◽  
Fluid Load ◽  
Single Nephron ◽  
Wistar Kyoto ◽  
Ultrafiltration Pressure

Clearance and micropuncture studies were conducted on 6-wk-old spontaneously hypertensive rats (SHR) of the Okamoto-Aoki strain and normotensive Wistar-Kyoto rats (WKY) under euvolemic conditions. Mean arterial pressure in SHR was elevated by 18 mmHg and their kidneys were vasoconstricted with reduced blood flow; resistances in preglomerular vessels and efferent arterioles were elevated 2.8 and 2 times, respectively, above WKY values. Whole kidney glomerular filtration rate (GFR) and single nephron glomerular filtration rate (SNGFR), based on fluid collection from either proximal or distal convolutions, were 25-30% lower in SHR. Fractional reabsorptions of fluid load by the proximal convoluted tubule (43%) and by the loop of Henle (52-55%) were similar in both groups. Accordingly, SHR exhibited less fluid delivery from the proximal convolution (8 vs. 12 nl/min) and to the distal convolution (3 vs. 5 nl/min). Glomerular dynamics in hypertensive and normotensive strains were characterized by filtration pressure disequilibrium. Estimated glomerular capillary pressure and mean effective ultrafiltration pressure were similar in SHR and WKY. SHR had a lower glomerular ultrafiltration coefficient than WKY (0.011 vs. 0.016 nl X s-1 X mmHg-1), which, combined with a lower glomerular plasma flow (41 vs. 73 nl/min), quantitatively accounted for the lower SNGFR in 6-wk-old SHR. These findings document important differences in renal function in young SHR compared with WKY that may participate in the development of hypertension.

scholarly journals Nitric oxide mediates anomalous tubuloglomerular feedback in rats fed high-NaCl diet after subtotal nephrectomy

2019 ◽  
Vol 316 (2) ◽  
pp. F223-F230 ◽  
Author(s):  
Scott C. Thomson
Keyword(s):  
Nitric Oxide ◽  
Tubuloglomerular Feedback ◽  
Cross Term ◽  
Nitric Oxide Signaling ◽  
Subtotal Nephrectomy ◽  
Single Nephron ◽  
Nos Inhibitor ◽  
Tubular Flow ◽  
Fluid Collections ◽  
Distal Delivery

Tubuloglomerular feedback (TGF) responses become anomalous in rats fed high-NaCl diet after subtotal nephrectomy (STN), such that stimulating TGF causes single nephron GFR (SNGFR) to increase rather than decrease. Micropuncture experiments were performed to determine whether this anomaly results from heightened nitric oxide response to distal delivery, which is a known mechanism for resetting TGF, or from connecting tubule TGF (cTGF), which is a novel amiloride-inhibitable system for offsetting TGF responses. Micropuncture was done in Wistar Froemter rats fed high-NaCl diet (HS) for 8–10 days after STN or sham nephrectomy. TGF was manipulated by orthograde microperfusion of Henle’s loop with artificial tubular fluid with or without NOS inhibitor, LNMMA, or the cell-impermeant amiloride analog, benzamil. SNGFR was measured by inulin clearance in tubular fluid collections from the late proximal tubule. TGF responses were quantified as the increase in SNGFR that occurred when the perfusion rate was reduced from 50 to 8 nl/min in STN or 40 to 8 nl/min in sham animals. The baseline TGF response was anomalous in STN HS (−4 ± 3 vs 14 ± 3 nl/min, P < 0.001). TGF response was normalized by perfusing STN nephron with LNMMA (14 ± 3 nl/min, P < 0.005 for ANOVA cross term) but not with benzamil (−3 ± 4 nl/min, P = 0.4 for ANOVA cross term). Anomalous TGF occurs in STN HS due to heightened effect of tubular flow on nitric oxide signaling, which increases to the point of overriding the normal TGF response. There is no role for cTGF in this phenomenon.

Renal effects of endogenous prostaglandin synthesis promoter ONO-3122

1992 ◽  
Vol 262 (6) ◽  
pp. F1047-F1054
Author(s):  
T. Takabatake ◽  
H. Hara ◽  
Y. Ishida ◽  
H. Ohta ◽  
K. Kobayashi
Keyword(s):  
Proximal Tubule ◽  
Prostaglandin Synthesis ◽  
Fluid Replacement ◽  
Tubuloglomerular Feedback ◽  
Loop Of Henle ◽  
Distal Nephron ◽  
Water Reabsorption ◽  
Renal Vasculature ◽  
Renal Effects ◽  
Collecting Tubules

The renal effects of a prostaglandin synthesis agonist, 1-iodo-3-aminomethyl-5,6,7,8-tetrahydro-2-naphthol (ONO-3122), were investigated in anesthetized rats. ONO-3122 (0.3 mg/kg + 0.3 mg.kg-1.h-1 iv) doubled the urinary excretion of the main metabolites of prostaglandin F, and induced transient increases in renal blood flow and glomerular filtration rate (GFR) with a marked, stable natriuresis. Indomethacin suppressed the natriuresis. When the diuretic fluid losses were replaced, micropuncture showed an unaltered reabsorption of sodium in the proximal tubule but reductions in the loop of Henle (86 +/- 1 vs. 76 +/- 1%) and in the more distal segments (98 +/- 1 vs. 83 +/- 3%) with comparable reductions in water reabsorption. Potassium secretion was seen in the distal and collecting tubules. Without fluid replacement, sodium reabsorption was reduced in the loop and more distal nephron but increased in the proximal tubule. Differences between proximal and distal nephron GFR were unaffected by systemic ONO-3122. Loop perfusion with ONO-3122 did not change tubuloglomerular feedback responses, which were, however, completely suppressed by furosemide. It is concluded that ONO-3122 stimulates renal prostaglandin biosynthesis, transiently dilates renal vasculature, and induces natriuresis mainly by suppressing sodium and water reabsorption in the loop of Henle and the more distal nephron. Luminal ONO-3122 does not affect the tubuloglomerular feedback.

Neuronal NOS contributes to biphasic autoregulatory response during enhanced TGF activity

1999 ◽  
Vol 277 (1) ◽  
pp. F113-F120 ◽  
Author(s):  
Atsuhiro Ichihara ◽  
L. Gabriel Navar
Keyword(s):  
Initial Response ◽  
Renal Perfusion ◽  
Tubuloglomerular Feedback ◽  
Afferent Arterioles ◽  
Series Of Experiments ◽  
Oxide Synthase ◽  
Increased Activity ◽  
Arteriolar Diameter ◽  
Distal Delivery

To assess the afferent arteriolar autoregulatory response during increased activity of the tubuloglomerular feedback (TGF) mechanism and to delineate the contribution of neuronal nitric oxide synthase (nNOS) to this response, afferent arteriolar diameter responses to changes in renal perfusion pressure (RPP) were monitored in vitro using the blood-perfused rat juxtamedullary nephron preparation. At RPP of 100 mmHg, basal afferent arteriolar diameter averaged 21.1 ± 1.4 μm ( n = 9). The initial and sustained constrictor responses of afferent arterioles to a 60-mmHg increase in RPP averaged 14.8 ± 1.4% and 13.3 ± 1.3%, respectively. Acetazolamide treatment, which enhances TGF responsiveness by increasing distal nephron volume delivery, significantly decreased basal afferent arteriolar diameter by 8.2 ± 0.5% and enhanced the initial response (25.5 ± 2.3%) to a 60-mmHg increase in RPP but did not alter the sustained response (14.3 ± 1.5%). In another series of experiments, nNOS inhibition with 10 μM S-methyl-l-thiocitrulline (l-SMTC) significantly decreased afferent arteriolar diameter from 20.3 ± 1.3 to 18.3 ± 1.1 μm ( n = 7) and enhanced both the initial (34.4 ± 3.5%) and sustained constrictor responses (27.6 ± 2.9%) to a 60-mmHg increase in RPP. Treatment with acetazolamide further enhanced both initial (56.4 ± 3.0%) and sustained responses (54.6 ± 2.7%). Interruption of distal delivery by transection of the loops of Henle prevented the enhanced responses to increases in RPP elicited with either acetazolamide orl-SMTC. These results indicate that nNOS contributes to the counteracting resetting process of biphasic afferent arteriolar constrictor responses to increases in RPP through a TGF-dependent mechanism.

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