Combined Effects of Carbonic Anhydrase Inhibitor and Adenosine A&lt;sub&gt;1&lt;/sub&gt; Receptor Antagonist on Hemodynamic and Tubular Function in the Kidney

Miracle, Cynthia M.; Rieg, Timo; Blantz, Roland C.; Vallon, Volker; Thomson, Scott C.

doi:10.1159/000108625

Cited by 15 publications

(15 citation statements)

References 74 publications

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“…Our previous micropuncture studies suggested a role for NBCe1 in mediating the acute diuretic effect in response to selective adenosine A 1 receptor blockade (40). To further examine a potential role of NBCe1 for mediating the caffeine effects, we randomized control mice to treatment with DIDS [nonselective NBCe1 inhibitor (23,35)] or vehicle 30 min prior to application of caffeine.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike the clear effect of PTH on Npt2a (within a similar time frame) (13), caffeine administration had no significant effect on Npt2a distribution or abundance. Our previous micropuncture experiments employing KW3902 indicated that Na ϩ /bicarbonate transporters may be responsible for KW3902-induced diuresis and natriuresis (40). NBCe1 accounts for the reabsorption of ϳ80% of filtered bicarbonate (30) and, like NHE3 and Npt2a, is regulated via the protein kinase A/cAMP pathway (20,21).…”

Section: Discussionmentioning

confidence: 99%

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Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3

Fenton

Poulsen

Chavez

et al. 2015

American Journal of Physiology-Renal Physiology

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Caffeine is one of the most widely consumed behavioral substances. We have previously shown that caffeine- and theophylline-induced inhibition of renal reabsorption causes diuresis and natriuresis, an effect that requires functional adenosine A1 receptors. In this study, we tested the hypothesis that blocking the Gi protein-coupled adenosine A1 receptor via the nonselective adenosine receptor antagonist caffeine changes Na(+)/H(+) exchanger isoform 3 (NHE3) localization and phosphorylation, resulting in diuresis and natriuresis. We generated tubulus-specific NHE3 knockout mice (Pax8-Cre), where NHE3 abundance in the S1, S2, and S3 segments of the proximal tubule was completely absent or severely reduced (>85%) in the thick ascending limb. Consumption of fluid and food, as well as glomerular filtration rate, were comparable in control or tubulus-specific NHE3 knockout mice under basal conditions, while urinary pH was significantly more alkaline without evidence for metabolic acidosis. Caffeine self-administration increased total fluid and food intake comparably between genotypes, without significant differences in consumption of caffeinated solution. Acute caffeine application via oral gavage elicited a diuresis and natriuresis that was comparable between control and tubulus-specific NHE3 knockout mice. The diuretic and natriuretic response was independent of changes in total NHE3 expression, phosphorylation of serine-552 and serine-605, or apical plasma membrane NHE3 localization. Although caffeine had no clear effect on localization of the basolateral Na(+)/bicarbonate cotransporter NBCe1, pretreatment with DIDS inhibited caffeine-induced diuresis and natriuresis. In summary, NHE3 is not required for caffeine-induced diuresis and natriuresis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3

Fenton

Poulsen

Chavez

et al. 2015

American Journal of Physiology-Renal Physiology

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“…Tubular fluid chloride concentration was determined by the electrometric titration method of Ramsey et al (10) as modified by Windhager and Giebisch (28) and as previously applied by us (9). Urinary Na and K were assayed by flame photometry (Cole Parmer).…”

Section: Methodsmentioning

confidence: 99%

Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat

Thomson

Rieg

Miracle

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 302: R75-R83, 2012. First published September 21, 2011 doi:10.1152/ajpregu.00357.2011.-Tubuloglomerular feedback (TGF) stabilizes nephron function from minute to minute and adapts to different steady-state inputs to maintain this capability. Such adaptation inherently renders TGF less efficient at buffering long-term disturbances, but the magnitude of loss is unknown. We undertook the present study to measure the compromise between TGF and TGF adaptation in transition from acute to chronic decline in proximal reabsorption (Jprox). As a tool, we blocked proximal tubule sodium-glucose cotransport with the SGLT2 blocker dapagliflozin in hyperglycemic rats with early streptozotocin diabetes, a condition in which a large fraction of proximal fluid reabsorption owes to SGLT2. Dapagliflozin acutely reduced proximal reabsorption leading to a 70% increase in early distal chloride, a saturated TGF response, and a major reduction in single nephron glomerular filtration rate (SNGFR). Acute and chronic effects on Jprox were indistinguishable. Adaptations to 10 -12 days of dapagiflozin included increased reabsorption by Henle's loop, which caused a partial relaxation in the increased tone exerted by TGF that could be explained without desensitization of TGF. In summary, TGF contributes to long-term fluid and salt balance by mediating a persistent decline in SNGFR as the kidney adapts to a sustained decrease in Jprox.dapagliflozin; hyperfiltration AN ONGOING DISTURBANCE IN salt transport anywhere along the nephron will eventually be compensated by a combination of changes in glomerular filtration of salt, salt transport elsewhere along the nephron, and salt intake to fulfill the requirement for long-term balance. The kidney cannot obviate this requirement, but exerts some control over how it is achieved. Tubuloglomerular feedback (TGF) is one mechanism that the kidney can employ to influence how the response to an outside disturbance is compensated. TGF senses the amount of fluid and salt reaching the macula densa and evokes counterbalancing changes in single nephron glomerular filtration rate (SNGFR), thereby reducing the impact that an outside disturbance in proximal reabsorption would otherwise have on distal delivery. The usual way to measure the effectiveness of TGF is by in vivo micropuncture, which is most adapted to studying the TGF responses to events that occur on a time scale of several minutes (17). TGF responses over periods of 1-2 h have been partially characterized using carbonic anhydrase inhibitors to perturb proximal reabsorption (3). But little is known about the influence of TGF over the compensatory response to an outside disturbance lasting several days, which is the critical time frame over which the kidney regulates salt balance and blood pressure (5).The present studies were performed to...

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“…In a separate set of control and diabetic rats (n ϭ 7-8/group), Li ϩ clearance was measured according to a previously published procedure (32). Briefly, the animals were subjected to the surgical protocol described above (see Surgical procedures), except only the bladder was catheterized for urine collection, and the subcostal flank incision and the immobilization of the kidney with the plastic cup were not performed.…”

Section: Estimations Of Proximal Tubular Reabsorption Using LI ϩ Cleamentioning

confidence: 99%

Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption

Nordquist

Brown

Fasching

et al. 2009

American Journal of Physiology-Renal Physiology

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C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (T(Na)) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (QO2), T(Na), fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent QO2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (-24%), stop-flow pressure (-8%), and filtration fraction (-17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline T(Na) (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline QO2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.

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Combined Effects of Carbonic Anhydrase Inhibitor and Adenosine A<sub>1</sub> Receptor Antagonist on Hemodynamic and Tubular Function in the Kidney

Cited by 15 publications

References 74 publications

Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3

Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3

Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat

Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption

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