Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis

Y. Zhang; A. K. Mircheff; C. B. Hensley; C. E. Magyar; D. G. Warnock; R. Chambrey; K. -P. Yip; D. J. Marsh; N. -H. Holstein-Rathlou; A. A. McDonough

doi:10.1152/ajprenal.1996.271.1.f242-t

Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.1.f242-t ◽

1996 ◽

Vol 271 (1) ◽

pp. F242-F242

Author(s):

Y. Zhang ◽

A. K. Mircheff ◽

C. B. Hensley ◽

C. E. Magyar ◽

D. G. Warnock ◽

...

Keyword(s):

Original Artwork ◽

Low Resolution ◽

Sodium Transporters ◽

Pressure Natriuresis

Pages F1004'F1014: Y. Zhang, A. K. Mircheff, C. B. Hensley, C. E. Magyar, D. G. Warnock, R. Chambrey, K.-P. Yip, D. J. Marsh, N.-H. Holstein-Rathlou, and A. A. McDonough. “Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis.” The immunoblot panels in Figures 2 and 5–7 were inadvertently printed from low-resolution copies of the original artwork; in addition, the panels in Fig. 6 were incorrectly labeled. The correct figures are reproduced on the following pages. (See PDF)

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Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.4.r955-r ◽

1996 ◽

Vol 271 (4) ◽

pp. R955-R955

Author(s):

Y. Zhang ◽

A. K. Mircheff ◽

C. B. Hensley ◽

C. E. Magyar ◽

D. G. Warnock ◽

...

Keyword(s):

Original Artwork ◽

Low Resolution ◽

Sodium Transporters ◽

Pressure Natriuresis

Pages F1004–F1014: Y. Zhang, A. K. Mircheff, C. B. Hensley, C. E. Magyar, D. G. Warnock, R. Chambrey, K.-P. Yip, D. J. Marsh, N.-H. Holstein-Rathlou, and A. A. McDonough. “Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis.” The immunoblot panels in Figures 2 and 5–7 were inadvertently printed from low-resolution copies of the original artwork; in addition, the panels in Fig. 6 were incorrectly labeled. The correct figures are reproduced on the following pages. (See PDF)

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Impact of angiotensin II-mediated stimulation of sodium transporters in the nephron assessed by computational modeling

AJP Renal Physiology ◽

10.1152/ajprenal.00335.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. F1656-F1668 ◽

Cited By ~ 2

Author(s):

Aurélie Edwards ◽

Alicia A. McDonough

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Ang Ii ◽

Sodium Transporters ◽

Short And Long Term ◽

Physiological Impact ◽

Pressure Natriuresis ◽

Excretion Rates ◽

Volume Output

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na+ reabsorption. The effects of ANG II on tubular Na+ transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short- and long-term ANG II-induced transporter activation on Na+ and K+ reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng·kg−1·min−1 is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na+/H+ exchanger 3 (NHE3) or activated Na+-K+-2Cl− cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na+ excretion, yet there was no observed change in urine Na+. The lack of antinatriuresis, despite Na+ transporter accumulation, was supported by Li+ and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng·kg−1·min−1 raises blood pressure and increases Na+ transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na+ and volume output are increased, evidence for pressure natriuresis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na+ reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K+ while minimizing Na+ retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na+-Cl− cotransporter counteracts epithelial Na+ channel-induced urinary K+ loss.

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Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis

AJP Renal Physiology ◽

10.1152/ajprenal.1996.270.6.f1004 ◽

1996 ◽

Vol 270 (6) ◽

pp. F1004-F1014 ◽

Cited By ~ 47

Author(s):

Y. Zhang ◽

A. K. Mircheff ◽

C. B. Hensley ◽

C. E. Magyar ◽

D. G. Warnock ◽

...

Keyword(s):

Arterial Pressure ◽

Gradient Centrifugation ◽

Basolateral Membrane ◽

Tubuloglomerular Feedback ◽

Intracellular Membrane ◽

Acute Hypertension ◽

Sodium Transporters ◽

Pump Activity ◽

Pressure Natriuresis ◽

Na Uptake

Acute arterial hypertension provokes a rapid decrease in proximal tubule (PT) Na+ reabsorption, increasing flow to the macula densa, the signal for tubuloglomerular feedback. We tested the hypothesis, in rats, that Na+ transport is decreased due to rapid redistribution of apical Na+/H+ exchangers and basolateral Na+ pumps to internal membranes. Arterial pressure was increased 50 mmHg by constricting various arteries. We also tested whether transporter internalization occurred when PT Na+ reabsorption was inhibited with the carbonic anhydrase inhibitor benzolamide. Five minutes after initiating either natriuretic stimuli, cortex was removed, and membranes were fractionated by density gradient centrifugation. Urine output and endogenous lithium clearance increased threefold in response to either stimuli. Acute hypertension provoked a redistribution of apical Na+/H+ exchanger NHE3, alkaline phosphatase, and dipeptidyl peptidase IV to higher density membranes enriched in the intracellular membrane markers. Basolateral membrane Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity decreased 50%, 25-30% of the alpha 1-and beta 1-subunits redistributed to higher density membranes, and the remainder is attributed to decreased activity of the transporters. Benzolamide did not alter Na+ transporter activity or distribution, implying that decreasing apical Na+ uptake does not initiate redistribution or inhibition of basolateral Na(+)-K(+)-ATPase. We conclude that PT natriuresis provoked by acute arterial pressure is mediated by both endocytic removal of apical Na+/H+ exchangers and basolateral Na+ pumps as well as decreased total Na+ pump activity.

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Sex differences in adaptive downregulation of pre-macula densa sodium transporters with ANG II infusion in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00088.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. F187-F195 ◽

Cited By ~ 12

Author(s):

Swasti Tiwari ◽

Lijun Li ◽

Shahla Riazi ◽

Veerendra K. Madala Halagappa ◽

Carolyn M. Ecelbarger

Keyword(s):

Sex Differences ◽

Plasma Testosterone ◽

Sodium Reabsorption ◽

Thick Ascending Limb ◽

Ang Ii ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Sodium Transporters ◽

Pressure Natriuresis

An increase in blood pressure (BP) due to angiotensin II (ANG II) infusion or other means is associated with adaptive pressure natriuresis due to reduced sodium reabsorption primarily in proximal tubule (PT) and thick ascending limb (TAL). We tested the hypothesis that male and female mice would show differential response to ANG II infusion with regard to the regulation of the protein abundance of sodium transporters in the PT and TAL and that these responses would be modulated by aging. Young (∼3 mo) and old (∼21 mo) male and female mice were infused with ANG II at 800 ng·kg body wt−1·min−1 by osmotic minipump for 7 days or received a sham operation. ANG II increased mean arterial pressure (MAP), measured by radiotelemetry, significantly more in male mice of both ages (increased ∼30–40 mmHg), compared with females (increased ∼15–25 mmHg). On day 1, MAP was also significantly increased in old mice, relative to young ( P = 0.01). ANG II infusion was associated with a significant decline in plasma testosterone (to <30% of control male) in male mice and rise in young female mice (to 478% of control female). No sex differences were found in the upregulation of the sodium hydrogen exchanger abundance on Western blots observed with ANG II infusion or the downregulation of the sodium phosphate cotransporter; however, aging did impact on some of these changes. Male mice (especially young) also had significantly reduced levels of the TAL bumetanide-sensitive Na-K-2Cl cotransporter (to 60% of male control), while young females showed an increase (to 126% of female control) with ANG II infusion. These sex differences do not support impaired pressure natriuresis in male mice, but might reflect a greater need and attempt to mount an appropriately BP-metered natriuretic response by additional downregulation of TAL sodium reabsorption.

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Inflammatory cytokines regulate renal sodium transporters: how, where, and why?

AJP Renal Physiology ◽

10.1152/ajprenal.00465.2016 ◽

2017 ◽

Vol 313 (2) ◽

pp. F141-F144 ◽

Cited By ~ 19

Author(s):

Allison E. Norlander ◽

Meena S. Madhur

Keyword(s):

Blood Pressure ◽

Inflammatory Cytokines ◽

Critical Role ◽

Premature Death ◽

Common Pathway ◽

Sodium Transporters ◽

Adaptive Immune ◽

The Past ◽

Adaptive Immune Cells ◽

Pressure Natriuresis

Hypertension is growing in epidemic proportions worldwide and is now the leading preventable cause of premature death. For over a century, we have known that the kidney plays a critical role in blood pressure regulation. Specifically, abnormalities in renal sodium transport appear to be a final common pathway that gives rise to elevated blood pressure regardless of the nature of the initial hypertensive stimulus. However, it is only in the past decade that we have come to realize that inflammatory cytokines secreted by innate and adaptive immune cells, as well as renal epithelial cells, can modulate the expression and activity of sodium transporters all along the nephron, leading to alterations in pressure natriuresis, sodium and water balance, and ultimately hypertension. This mini-review highlights specific cytokines and the transporters that they regulate and discusses why inflammatory cytokines may have evolved to serve this function.

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Renocardiac protective effects of SGLT2 inhibitor combined with angiotensin receptor blocker in salt sensitive Dahl rats

European Heart Journal ◽

10.1093/eurheartj/ehab724.3415 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

H Ito ◽

K Dohi ◽

Y Zhe ◽

Y Ali ◽

K Katayama ◽

...

Keyword(s):

Combination Treatment ◽

Sglt2 Inhibitor ◽

Salt Sensitivity ◽

High Salt ◽

Protein Expression Level ◽

High Salt Diet ◽

Salt Diet ◽

Sodium Transporters ◽

Cont Group ◽

Pressure Natriuresis

Abstract Background Kidney plays a central role in regulating salt-sensitivity of blood pressure (BP) to governs sodium excretion via several mechanisms including pressure natriuresis and the actions of renal sodium transporters. Purpose We clarified the effects of combination treatment of sodium-glucose cotransporter 2 (SGLT2) inhibitor and angiotensin receptor blocker (ARB) on BP and the pathogenesis of renocardiac injuries, and elucidated underlying molecular mechanisms involved in the regulation of renal sodium handling in the development of salt-sensitivity by comparing with each monotreatment in Dahl salt-sensitive (DSS) hypertensive rats. Methods DSS rats were treated orally for 8-weeks with normal salt diet (0.3% NaCl) (NS/Cont group), high salt diet (8% NaCl) (HS/Cont group), high salt diet with ipragliflozin (0.04%) (HS/Ipra group), high salt diet with losartan (0.05%) (HS/Los group), or high salt diet with combination of ipragliflozin and losartan (HS/Ipra+Los group). Results The combination group significantly reduced systolic BP compared with either high salt diet control group, losartan or ipragliflozin monotreatment groups (HS/Ipra+Los: 182.5±18.4mmHg vs HS/Cont: 227.7±26.1; HS/Ipra: 216.6±26.9; HS/Los: 208.6±21.6, at 8-weeks of treatment, P<0.05, respectively) (Figure 1A). The slope of pressure-natriuresis curve was significantly increased in the HS/Ipra+Los group compared to that in the HS/Cont group (interaction P=0.024), HS/Ipra group (P=0.009), and HS/Los group (P=0.084) using the linear regression model (Figure 1B), which indicated that only the combination treatment of ipragliflozin and losartan improved salt-sensitivity. The combined treatment significantly improved creatinine clearance (HS/Ipra+Los: 3.3±0.9mL/min vs HS/Cont: 1.1±0.5; HS/Ipra: 1.7±0.6; HS/Los: 1.9±0.8, P<0.05, respectively). The combination treatment also significantly ameliorated glomerulosclerosis, and improved cardiomyocyte hypertrophy and perivascular fibrosis (Figure 1C). Angiotensin II type 1 receptor (AT1R) protein expression level in the kidney was remarkably suppressed in the combination treatment group compared to the other high salt diet groups. The protein expression level of Na+/H+ exchanger isoform 3 (NHE3) and Na+-K+-Cl– cotransporter 2 (NKCC2), two of major sodium transports in the renal tubules, were significantly decreased with losartan monotreatment and combination treatment, but not with ipragliflozin monotreatment (Figure 2). Conclusions The dual inhibition of SGLT2 and AT1R effectively improved salt-sensitivity via reducing renal expression levels of the sodium transporters, which eventually lead to renocardiac protection. Thus, the combination treatment could be a novel and useful therapeutic strategy for treating salt-sensitive hypertension and renal injury in non-diabetic patients. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research

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