RAPID COMMUNICATIONIn vivo inhibition of renal 11β-hydroxysteroid dehydrogenase in the rat stimulates collecting duct sodium reabsorption

2001 ◽  
Vol 101 (2) ◽  
pp. 195-198 ◽  
Author(s):  
M. A. BAILEY ◽  
R. J. UNWIN ◽  
D. G. SHIRLEY
Keyword(s):  
Collecting Duct ◽  
Hydroxysteroid Dehydrogenase ◽  
Sodium Reabsorption ◽  
High Dose ◽  
Mineralocorticoid Receptors ◽  
Distal Nephron ◽  
Urinary Recovery ◽  
Distal Tubules ◽  
Adrenalectomized Rats

In order to test the proposal that the aldosterone specificity of mineralocorticoid receptors in the collecting duct depends on inactivation of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD), we have assessed the effect of pharmacological inhibition of 11β-HSD on collecting duct Na+ reabsorption in vivo. Adrenalectomized rats (n = 14) were infused intravenously with high-dose corticosterone, and late-distal tubules were perfused orthogradely with artificial tubular fluid containing [14C]inulin and 22Na; urinary recoveries of the radioisotopes were monitored. Half of the rats received intravenous carbenoxolone to inhibit renal 11β-HSD activity. The urinary recovery of [14C]inulin was complete in both groups of animals (101ŷ2% versus 101ŷ3%), but the recovery of 22Na was lower in carbenoxolone-treated rats (34ŷ5%) than in the corticosterone-alone group (54ŷ4%, P < 0.01). These data, which provide the first demonstration of enhanced Na+ reabsorption in the distal nephron during inhibition of renal 11β-HSD in vivo, strongly support the proposal that 11β-HSD normally prevents endogenous glucocorticoid from exerting mineralocorticoid-like effects.

Distal tubular electrolyte transport during inhibition of renal 11β-hydroxysteroid dehydrogenase

2001 ◽  
Vol 280 (1) ◽  
pp. F172-F179 ◽  
Author(s):  
Katharine J. Biller ◽  
Robert J. Unwin ◽  
David G. Shirley
Keyword(s):  
Distal Tubule ◽  
Hydroxysteroid Dehydrogenase ◽  
Treated Group ◽  
High Dose ◽  
Mineralocorticoid Receptors ◽  
Distal Nephron ◽  
Collecting Ducts ◽  
Micropuncture Study ◽  
Stimulation Of

To test the proposal that the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) confers aldosterone specificity on mineralocorticoid receptors in the distal nephron by inactivating glucocorticoids, we performed a free-flow micropuncture study of distal tubular function in adrenalectomized rats infused with high-dose corticosterone. One-half of the rats were additionally given intravenous carbenoxolone (CBX; 6 mg/h) to inhibit renal 11β-HSD activity. Although this maneuver lowered fractional Na+ excretion (1.1 ± 0.2 vs. 1.9 ± 0.2%, P < 0.01), Na+ reabsorption within the accessible distal tubule was found to be similar in the two groups of animals. In contrast, distal tubular K+ secretion was enhanced in CBX-treated rats: fractional K+ deliveries to the early and late distal collection sites in the corticosterone-alone group were 13 ± 1 and 20 ± 3%, respectively (not significant), whereas corresponding data in the CBX-treated group were 9 ± 1 and 24 ± 2% ( P < 0.01). This stimulation of distal K+ secretion provides the first direct in vivo evidence that 11β-HSD normally prevents corticosterone from exerting a mineralocorticoid-like effect in the distal tubule. The reduction in fractional Na+ excretion during inhibition of 11β-HSD, in the absence of a change in end-distal Na+delivery, suggests enhanced Na+ reabsorption in the collecting ducts.

Inhibition of renal 11β-hydroxysteroid dehydrogenase in vivo by carbenoxolone in the rat and its relationship to sodium excretion

1998 ◽  
Vol 95 (4) ◽  
pp. 435-443 ◽  
Author(s):  
K. J. SEWELL ◽  
D. G. SHIRLEY ◽  
A. E. MICHAEL ◽  
A. THOMPSON ◽  
D. P. NORGATE ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Poor Correlation ◽  
High Dose ◽  
Mineralocorticoid Receptors ◽  
Distal Nephron ◽  
Electrolyte Excretion ◽  
Dependent Inhibition ◽  
Anaesthetized Rats ◽  
High Doses

1.The type 2 isoform of 11β-hydroxysteroid dehydrogenase, an enzyme which converts cortisol or corticosterone to inactive 11-ketosteroid metabolites, is thought to be responsible for preventing access of endogenous glucocorticoids to mineralocorticoid receptors in the distal nephron; although direct in vivo evidence for this is still lacking. We have examined whether graded inhibition of renal 11β-hydroxysteroid dehydrogenase activities in vivo results in corresponding changes in urinary electrolyte excretion due to exposure of mineralocorticoid receptors to circulating endogenous glucocorticoids. 2.Anaesthetized rats were infused intravenously with vehicle alone or with one of three doses of carbenoxolone: 0.06, 0.6 or 6 ;mg/h. After measurement of renal electrolyte excretion, the kidneys were snap-frozen in liquid nitrogen and 11β-hydroxysteroid dehydrogenase activities were measured directly by enzyme assay in the presence of NAD+ or NADP+. 3.A dose-dependent inhibition of renal 11β-hydroxysteroid dehydrogenase activities was observed: the low, intermediate and high doses of carbenoxolone causing approximately 50%, 80% and > 90% inhibition respectively. Only with the high dose was an effect on renal function observed (decreased fractional Na+ excretion and urinary Na+/K+ ratio). 4.The poor correlation between the extent of inhibition of renal 11β-hydroxysteroid dehydrogenase and altered urinary Na+ excretion, apparent at the lower doses of carbenoxolone, suggests either that 11β-hydroxysteroid dehydrogenase has considerable functional reserve, or that it may not be the only mechanism determining mineralocorticoid receptor specificity in the distal nephron.

scholarly journals Collecting Duct Is a Site of Sodium Retention in PAN Nephrosis: A Rationale for Amiloride Therapy

2001 ◽  
Vol 12 (3) ◽  
pp. 598-601 ◽  
Author(s):  
GEORGES DESCHÊNES ◽  
MONIKA WITTNER ◽  
ANTONIO DI STEFANO ◽  
SYLVIE JOUNIER ◽  
ALAIN DOUCET
Keyword(s):  
Collecting Duct ◽  
Urinary Sodium Excretion ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
Puromycin Aminonucleoside ◽  
Aldosterone Receptor ◽  
Collecting Tubules ◽  
A Site

Abstract. Micropuncture studies of the distal nephron and measurements of Na,K-ATPase activity in microdissected collecting tubules have suggested that renal retention of sodium in puromycin aminonucleoside (PAN) nephrotic rats originates in the collecting duct. The present study demonstrated this hypothesis by in vitro microperfusion and showed that amiloride was able to restore sodium balance. Indeed, isolated perfused cortical collecting ducts from PAN-treated rats exhibited an abnormally high transepithelial sodium reabsorption that was abolished by amiloride, and in vivo administration of amiloride fully prevented decreased urinary sodium excretion and positive sodium balance in nephrotic rats. As expected from the aldosterone independence of Na+ retention in PAN nephrotic rats, blockade of aldosterone receptor by potassium canrenoate did not alter urinary Na+ excretion, Na+ balance, or ascites formation in PAN nephrotic rats.

Renal localization and actions of adrenomedullin: a natriuretic peptide

1995 ◽  
Vol 268 (4) ◽  
pp. F657-F663 ◽  
Author(s):  
M. Jougasaki ◽  
C. M. Wei ◽  
L. L. Aarhus ◽  
D. M. Heublein ◽  
S. M. Sandberg ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Collecting Duct ◽  
Plasma Concentrations ◽  
In Vivo Studies ◽  
Sodium Reabsorption ◽  
Contralateral Kidney ◽  
Arterial Blood ◽  
Group I

Adrenomedullin (ADM) is a newly described 52-amino acid peptide originally isolated from extracts of human pheochromocytoma and, more recently, detected in human plasma. Based on the report that ADM mRNA and immunoreactivity are present in the kidney, the current study was designed to determine the renal distribution of ADM by immunohistochemistry and the renal biological actions of ADM. In the immunohistochemical studies, the present investigation demonstrated the localization of ADM in glomeruli, cortical distal tubules, and medullary collecting duct cells of the normal canine kidney. In the in vivo studies, ADM was administered (0.25 ng.kg-1.min-1 in group I and 1, 5, and 25 ng.kg-1.min-1 in group II) intrarenally in normal mongrel dogs with the contralateral kidney receiving only saline vehicle. Intrarenal infusion of ADM resulted in a marked diuretic and natriuretic response, whereas the contralateral kidney showed no renal effects. These significant natriuresis and diuresis in the ADM kidney were associated with increases in glomerular filtration rate and fractional sodium excretion and with a decrease in distal tubular sodium reabsorption. Intrarenal infusion of ADM also caused an increase in mean arterial blood pressure and a decrease in heart rate. Plasma concentrations of atrial natriuretic peptide, renin activity, aldosterone, and guanosine 3',5'-cyclic monophosphate were not changed during the infusion of ADM. The current study demonstrates that ADM is present in renal glomerular and tubular cells and is a potent natriuretic peptide that may play an important role in the regulation of sodium excretion.

Micropuncture study of the effect of ANP on the papillary collecting duct in the rat

1988 ◽  
Vol 254 (4) ◽  
pp. F477-F483 ◽  
Author(s):  
A. van de Stolpe ◽  
R. L. Jamison
Keyword(s):  
Collecting Duct ◽  
Sodium Concentration ◽  
Sodium Reabsorption ◽  
Micropuncture Study ◽  
Papillary Collecting Duct ◽  
Group 3 ◽  
Group 2 ◽  
Tubule Fluid ◽  
Group 1

Micropuncture collections were obtained from the terminal collecting duct (CD) at base and tip of the renal papilla of the rat. Group 1 was studied before and during infusion with atrial natriuretic peptide (ANP), group 2 was administered the vehicle only, and group 3 received acetazolamide to increase sodium delivery to the base to a similar extent as after ANP. ANP caused a decrease in blood pressure, a slight increase in GFR, natriuresis, and diuresis. Sodium delivery to the collecting duct at the base of the papilla increased. Between base and tip, sodium reabsorption was inhibited. Tubule fluid sodium concentration (TFNa) was increased at the base and remained high at the tip; in contrast TFNa fell between base and tip in control and acetazolamide groups. After acetazolamide, sodium reabsorption in the terminal CD was not inhibited. These results demonstrate that in vivo ANP 1) increases the delivery of sodium to the terminal CD and 2) inhibits sodium reabsorption in the terminal CD. The findings for chloride were similar to those for sodium. ANP also increased delivery of H2O, K, Ca, and Mg to the CD at the papillary base but did not significantly affect their transport by the terminal CD.

Effect of calcitonin on urine concentration in the rat

1983 ◽  
Vol 244 (4) ◽  
pp. F432-F435 ◽  
Author(s):  
S. Carney ◽  
T. Morgan ◽  
C. Ray ◽  
L. Thompson
Keyword(s):  
Water Permeability ◽  
Partial Agonist ◽  
Collecting Duct ◽  
Free Water ◽  
Urine Concentration ◽  
Distal Nephron ◽  
Free Water Clearance ◽  
Normal Increase

Because mammalian distal nephron segments with both calcitonin- and antidiuretic hormone- (ADH) sensitive adenylate cyclase activity have been described, in vivo and in vitro experiments were performed to study the effect of calcitonin on rat distal nephron water permeability. Calcitonin 1 and 0.1 U/ml, but not 0.01 U/ml, significantly increased the diffusional water permeability in the isolated papillary collecting duct by 15 and 11%, respectively. However, this effect was small when compared with a 68% increase with a supramaximal concentration of ADH (from 4.0 +/- 0.3 to 6.7 +/- 0.9 microns/s; n = 6, P less than 0.01). The normal increase in water permeability with increasing concentration of ADH (0.02 and 0.2 mU/ml) was depressed by the previous addition of calcitonin (1 U/ml) to the bath but was unaltered with the supramaximal ADH concentration (2 mU/ml). Verapamil, a compound that antagonizes cellular calcium entry, did not alter the effect of calcitonin on diffusional water permeability. Calcitonin in concentrations of 0.05, 0.5, and 5 U/ml produced a significant reduction in urine flow and free water clearance. Pretreatment with calcitonin in these concentrations inhibited the antidiuretic action of ADH. These studies suggest that calcitonin acts as a partial agonist to ADH within the distal nephron. It is unclear whether such an action represents a physiological or a pharmacological effect.

scholarly journals ANP-mediated inhibition of distal nephron fractional sodium reabsorption in wild-type and mice overexpressing natriuretic peptide receptor

2010 ◽  
Vol 298 (1) ◽  
pp. F103-F108 ◽  
Author(s):  
Di Zhao ◽  
Kailash N. Pandey ◽  
L. Gabriel Navar
Keyword(s):  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Urinary Sodium Excretion ◽  
Sodium Reabsorption ◽  
Natriuretic Peptide Receptor ◽  
Distal Nephron ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Npr1 Gene

Atrial natriuretic peptide (ANP) elicits natriuresis; however, the relative contributions of proximal and distal nephron segments to the overall ANP-induced natriuresis have remained uncertain. This study was performed to characterize the effects of ANP on distal nephron sodium reabsorption determined after blockade of the two major distal nephron sodium transporters with amiloride (5 μg/g body wt) plus bendroflumethiazide (12 μg/g body wt) in male anesthetized C57/BL6 and natriuretic peptide receptor-A gene (Npr1) targeted four-copy mice. The lower dose of ANP (0.1 ng·g body wt−1·min−1, n = 6) increased distal sodium delivery (DSD, 2.4 ± 0.4 vs. 1.6 ± 0.2 μeq/min, P < 0.05) but did not change fractional reabsorption of DSD compared with control (86.3 ± 2.0 vs. 83.9 ± 3.6%, P > 0.05), thus limiting the magnitude of the natriuresis. In contrast, the higher dose (0.2 ng·g body wt−1·min−1, n = 6) increased DSD (2.8 ± 0.3 μeq/min, P < 0.01) and also decreased fractional reabsorption of DSD (67.4 ± 4.5%, P < 0.01), which markedly augmented the natriuresis. In Npr1 gene-duplicated four-copy mice ( n = 6), the lower dose of ANP increased urinary sodium excretion (0.6 ± 0.1 vs. 0.3 ± 0.1 μeq/min, P < 0.05) and decreased fractional reabsorption of DSD compared with control (72.2 ± 3.4%, P < 0.05) at similar mean arterial pressures (91 ± 6 vs. 92 ± 3 mmHg, P > 0.05). These results provide in vivo evidence that ANP-mediated increases in DSD alone exert modest effects on sodium excretion and that inhibition of fractional reabsorption of distal sodium delivery is requisite for the augmented natriuresis in response to the higher dose of ANP or in Npr1 gene-duplicated mice.

11 beta-Hydroxysteroid dehydrogenase mRNA expression in rat kidney

1991 ◽  
Vol 260 (5) ◽  
pp. F764-F767
Author(s):  
J. L. Yau ◽  
A. D. Van Haarst ◽  
M. P. Moisan ◽  
S. Fleming ◽  
C. R. Edwards ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Binding Sites ◽  
Mineralocorticoid Receptor ◽  
Rat Kidney ◽  
Hydroxysteroid Dehydrogenase ◽  
Mineralocorticoid Receptors ◽  
Tubular Cells ◽  
Renal Tubular

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) protects nonspecific renal mineralocorticoid receptors from exposure to circulating glucocorticoid in vivo by catalyzing the conversion of corticosterone to inactive 11-dehydrocorticosterone. Although 11 beta-OHSD bioactivity and aldosterone binding sites are found in distal tubular cells, mineralocorticoid receptor and 11 beta-OHSD immunoreactivities are not colocalized. However, there are several kidney isoforms of 11 beta-OHSD, not all of which may be immunoreactive, whereas only a single mRNA species has been described. Using in situ hybridization we found 11 beta-OHSD mRNA is highly expressed in all renal tubular epithelia in the rat. It is therefore likely that 11 beta-OHSD is colocalized with mineralocorticoid receptors in distal tubular cells.

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