Increased severity of renal impairment in nephritic mice lacking the EP1 receptor

Sherine Rahal; Lyne I. McVeigh; Yahua Zhang; Youfei Guan; Matthew D. Breyer; Chris R.J. Kennedy

doi:10.1139/y06-029

Increased severity of renal impairment in nephritic mice lacking the EP1 receptor

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y06-029 ◽

2006 ◽

Vol 84 (8-9) ◽

pp. 877-885 ◽

Cited By ~ 12

Author(s):

Sherine Rahal ◽

Lyne I. McVeigh ◽

Yahua Zhang ◽

Youfei Guan ◽

Matthew D. Breyer ◽

...

Keyword(s):

Renal Impairment ◽

Collecting Duct ◽

Urine Osmolality ◽

Permeability Barrier ◽

Receptor Subtypes ◽

Glomerular Permeability ◽

Targeted Deletion ◽

Matrix Expansion ◽

Ep1 Receptor ◽

Inflammatory Drugs

In experimental glomerulonephritis, inhibition of renal prostaglandin (PG) synthesis by nonsteroidal-anti-inflammatory drugs (NSAIDs) moderates proteinuria, yet can induce harmful effects on renal blood flow and Na+–K+–water balance thereby implicating 1 or more prostanoid receptor subtypes. We investigated the role of the PGE2 EP1 receptor in nephritis since it is expressed in the glomerulus, collecting duct and vasculature in which its activity might contribute to adaptive or maladaptive responses. Accordingly, a mouse model of accelerated antiglomerular basement membrane (anti-GBM) nephrotoxic serum (NTS) nephritis was induced in mice with targeted-deletion of the EP1 receptor (EP1−/−). Proteinuria was similar between wild-type (wt) and EP1−/− NTS groups, thus negating a role for this subtype in modulating the glomerular permeability barrier in this model of anti-GBM NTS. However, overall renal damage was more acute in NTS EP1−/− mice, as evidenced by the degree of glomerular mesangial matrix expansion and the frequency of tubular dilatations. These changes in renal pathology were accompanied by stronger impairment of renal function in NTS EP1−/− mice, such that levels of serum creatinine, urea, Na+, and K+ were each significantly higher than those observed in NTS wt mice. Lastly, compared with wt mice, induction of NTS more severely reduced urine osmolality and body mass in EP1−/− mice. Taken together, the increased renal impairment seen in NTS EP1−/− mice suggests that the EP1 subtype plays a compensatory role in the context of acute nephritis.

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Urinary concentrating function in mice lacking EP3 receptors for prostaglandin E2

AJP Renal Physiology ◽

10.1152/ajprenal.1998.275.6.f955 ◽

1998 ◽

Vol 275 (6) ◽

pp. F955-F961 ◽

Cited By ~ 24

Author(s):

Eric F. Fleming ◽

Krairek Athirakul ◽

Michael I. Oliverio ◽

Mikelle Key ◽

Jennifer Goulet ◽

...

Keyword(s):

Collecting Duct ◽

Renal Medulla ◽

Urine Osmolality ◽

Receptor Subtypes ◽

Cortical Collecting Duct ◽

Prostanoid Production ◽

Organ Systems ◽

Ep Receptor ◽

The Individual

The actions of prostaglandin (PG) E2 are mediated by four distinct classes of PGE2E-prostanoid (EP) receptors (EP1through EP4). However, the in vivo functions of the individual EP receptor subtypes have not been delineated. To study the functions of one of these subtypes, the EP3 receptor, we generated EP3-deficient (−/−) mice by gene targeting. EP3 −/− animals survived in expected numbers, reproduced, and had no obvious abnormalities in their major organ systems. Because the EP3 receptor is expressed at high levels in the renal medulla and cortical collecting duct, and because previous studies have suggested that the EP3 receptor might antagonize the effects of vasopressin in the distal nephron, we examined urinary concentrating functions in EP3−/− mice. Basal urine osmolality (UOsm) was similar in groups of EP3 −/− and wild-type (EP3 +/+) mice. However, after inhibition of endogenous PGE2 production by indomethacin, UOsm increased significantly in EP3 +/+ but not in EP3 −/− mice. Despite this insensitivity to acute inhibition of prostanoid production, EP3 −/− mice concentrated and diluted their urine normally in response to a series of physiological stimuli. This suggests that PGE2 acts through the EP3 receptor to modulate urinary concentrating mechanisms in the kidney, but these effects are not essential for normal regulation of urinary osmolality.

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AQP3, p-AQP2, and AQP2 expression is reduced in polyuric rats with hypercalcemia: prevention by cAMP-PDE inhibitors

AJP Renal Physiology ◽

10.1152/ajprenal.00040.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. F1313-F1325 ◽

Cited By ~ 33

Author(s):

Weidong Wang ◽

Chunling Li ◽

Tae-Hwan Kwon ◽

Mark A. Knepper ◽

Jørgen Frøkiær ◽

...

Keyword(s):

Vitamin D ◽

Collecting Duct ◽

Urine Osmolality ◽

Outer Medulla ◽

Camp Phosphodiesterase ◽

Aqp4 Expression ◽

Pde Inhibitors ◽

Aqp1 Expression ◽

Outer Stripe ◽

Inhibitor Treatment

The purpose of this study was to evaluate whether hypercalcemia is associated with downregulation of renal aquaporins (AQPs), including AQP1, AQP2, phosphorylated AQP2 (p-AQP2), AQP3, and AQP4, and if this is the case, to test whether cAMP-phosphodiesterase (PDE) inhibitor treatment can prevent AQP downregulation and prevent the development of polyuria. Vitamin D-induced hypercalcemia in rats was associated with increased urine output and reduced urine osmolality, consistent with previous findings (Levi M, Peterson L, and Berl T. Kidney Int 23: 489–497, 1983). Semiquantitative immunoblotting revealed a significant reduction in the abundance of inner medullary AQP2 (52 ± 6% of control levels), consistent with previous studies, and of AQP2, which is phosphorylated at the PKA phosphorylation consensus site serine 256 (p-AQP2; 36 ± 8%). Moreover, AQP3 abundance was also significantly decreased (45 ± 7 and 61 ± 6% of control levels in inner medulla and whole kidney, respectively). Consistent with this, immunohistochemistry demonstrated reduced AQP3 immunolabeling along the entire collecting duct. AQP4 expression was not reduced. Surprisingly, total kidney AQP1 abundance was also reduced (60 ± 6%). AQP1 expression was reduced in the cortex and outer stripe of the outer medulla (48 ± 7%; i.e., in proximal tubules). In contrast, AQP1 levels were not changed in the inner stripe of the outer medulla or in the inner medulla (i.e., descending thin limbs and vasa recta). Treatment with the cAMP-PDE inhibitors rolipram and milrinone in combination (inhibiting PDE IV and PDE III isoenzymes) at day 2 and onward completely prevented the hypercalcemia-induced downregulation of AQP2 and AQP3 (but not AQP1) and completely prevented the development of polyuria. In conclusion, AQP3, AQP2, and p-AQP2 are downregulated and are likely to play critical roles in the development of polyuria associated with vitamin D-induced hypercalcemia. Moreover, PDE inhibitor treatment significantly prevented the reduced expression of collecting duct AQPs and prevented the development of polyuria.

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Downregulation of renal vasopressin V2 receptor and aquaporin-2 expression parallels age-associated defects in urine concentration

AJP Renal Physiology ◽

10.1152/ajprenal.00403.2003 ◽

2004 ◽

Vol 287 (4) ◽

pp. F797-F805 ◽

Cited By ~ 37

Author(s):

Ying Tian ◽

Ryota Serino ◽

Joseph G. Verbalis

Keyword(s):

Collecting Duct ◽

Water Channel ◽

Age Groups ◽

Urine Osmolality ◽

Brown Norway ◽

Water Restriction ◽

Water Excretion ◽

F1 Hybrid ◽

Young Rats ◽

Aquaporin 2

Renal concentrating ability is known to be impaired with aging. The antidiuretic hormone AVP plays an important role in renal water excretion by regulating the membrane insertion and abundance of the water channel aquaporin-2 (AQP2); this effect is primarily mediated via the V2 subtype of the AVP receptor (V2R). This study evaluated the hypothesis that decreased renal sensitivity to AVP, with subsequent altered renal AQP2 expression, contributes to the reduced urinary concentrating ability with aging. Our results show that under baseline conditions, urine osmolality is significantly lower in aged Fischer 344 and Brown-Norway F1 hybrid (F344BN) rats despite equivalent plasma AVP concentrations as in young rats. Levels of kidney V2R mRNA expression and AQP2 abundances were also significantly decreased in aged F344BN rats, as was AQP2 immunostaining in collecting duct cells. In response to moderate water restriction, urine osmolality increased by significantly lesser amounts in aged F344BN rats compared with young rats despite similar increases in plasma AVP levels. Moderate water restriction induced equivalent relative increases in renal AQP2 abundances in all age groups but resulted in significantly lower abundances in total kidney AQP2 protein in aged compared with young F344BN rats. These results therefore demonstrate a functional impairment of renal concentrating ability in aged F344BN rats that is not due to impaired secretion of AVP but rather appears to be related to impaired responsiveness of the kidney to AVP that is secondary, at least in part, to a downregulation of renal V2R expression and AQP2 abundance.

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Endothelin receptor mRNA expression in renal medulla identified by in situ RT-PCR

AJP Renal Physiology ◽

10.1152/ajprenal.1995.269.3.f449 ◽

1995 ◽

Vol 269 (3) ◽

pp. F449-F457 ◽

Cited By ~ 19

Author(s):

L. H. Chow ◽

S. Subramanian ◽

G. J. Nuovo ◽

F. Miller ◽

E. P. Nord

Keyword(s):

Mrna Expression ◽

Collecting Duct ◽

Renal Medulla ◽

Receptor Subtypes ◽

Rt Pcr ◽

Receptor Mrna ◽

Pcr Products ◽

Medullary Collecting Duct ◽

Labeled Probe

Three subtypes of endothelin (ET) receptors have been identified by cDNA cloning, namely ET-RA, ET-RB, and ET-RC. In the current study the precise cellular distribution of the ET receptor subtypes in the renal medulla was explored by detecting the corresponding polymerase chain reaction (PCR)-amplified cDNAs by in situ reverse transcription (RT)-PCR. The PCR-amplified cDNAs were detected either by direct incorporation using digoxigenin-dUTP (dig-dUTP) as a nucleotide substrate in the PCR reaction or by in situ hybridization with the dig-dUTP-labeled probe. ET-RB mRNA was detected exclusively in the epithelial cells of the inner and outer medullary collecting duct. In contrast, ET-RA message was observed primarily in interstitial cells and pericytes of the vasae rectae in the outer and inner medulla. Southern blot analysis of PCR-amplified cDNAs reverse transcribed from extracted RNA of rat renal medulla confirmed the specificity of the RT-PCR products. ET-RC mRNA was not detected. We conclude that ET-RB is the major ET receptor found in rat renal medulla and is expressed exclusively on inner medullary collecting duct cells. The pattern of ET receptor mRNA expression described suggests different physiological actions for ET on the diverse cellular structures of the renal medulla.

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Role of endothelin receptor subtypes in the in vivo regulation of renal function

AJP Renal Physiology ◽

10.1152/ajprenal.1995.268.3.f455 ◽

1995 ◽

Vol 268 (3) ◽

pp. F455-F460 ◽

Cited By ~ 31

Author(s):

A. L. Clavell ◽

A. J. Stingo ◽

K. B. Margulies ◽

R. R. Brandt ◽

J. C. Burnett

Keyword(s):

Sodium Excretion ◽

Urine Osmolality ◽

Receptor Activation ◽

Receptor Subtypes ◽

Low Doses ◽

Renal Vasoconstriction ◽

Etb Receptor ◽

Diuretic Response

Endothelin (ET) is a potent vasoconstrictor peptide of endothelial origin, which at low doses results in renal vasoconstriction and diuresis with variable actions on sodium excretion. The current study conducted in four groups of anesthetized dogs was designed to define the role of the ETA and ETB receptor subtypes in the renal actions of low-dose exogenous ET. Group 1 (n = 4) animals served as time controls. In group 2 (n = 6) a systemic ET-1 (5 ng.kg-1.min-1) infusion mediated renal vasoconstriction, antinatriuresis with increases in proximal fractional reabsorption of sodium, and diuresis with a decrease in urine osmolality. In group 3 (n = 6) intrarenal BQ-123 (4 micrograms.kg-1.min-1), a selective ETA antagonist, abolished the systemic ET-1-mediated changes in renal hemodynamics and unmasked a natriuretic action at the level of the proximal tubule. In contrast, the diuretic response of ET was not altered by BQ-123. In group 4 (n = 6) intrarenal sarafotoxin 6-c, a selective ETB receptor agonist, resulted in a diuretic response without a change in sodium excretion. These studies suggest that the ETA receptor contributes to the renal vasoconstriction, whereas the ETB receptor is largely responsible for the diuretic response during exogenous ET. This study also suggests that at low doses ET is natriuretic in vivo by decreasing proximal tubular reabsorption of sodium independent of ETA or ETB receptor activation.

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Expression of mRNA for natriuretic peptide receptor subtypes in bovine kidney

AJP Renal Physiology ◽

10.1152/ajprenal.1994.267.2.f318 ◽

1994 ◽

Vol 267 (2) ◽

pp. F318-F324 ◽

Cited By ~ 3

Author(s):

T. Yamamoto ◽

L. Feng ◽

T. Mizuno ◽

S. Hirose ◽

K. Kawasaki ◽

...

Keyword(s):

Epithelial Cells ◽

Natriuretic Peptide ◽

Collecting Duct ◽

Biologically Active ◽

Ribonuclease Protection Assay ◽

Receptor Subtypes ◽

Total Rna ◽

Duct Cells ◽

Glomerular Epithelial Cells ◽

Collecting Duct Cells

The localization of mRNA for atrial natriuretic peptide (ANP) receptor subtypes (A, B, C) in the kidney was examined. Quantitative analysis of the ribonuclease protection assay showed that the numbers of type A receptor (ANPRA) mRNA were 6.9 x 10(7) in the glomeruli and 10.4 x 10(7) molecules/micrograms of total RNA in the inner medulla, and that of type C receptor (ANPRC) mRNA was 21.7 x 10(7) molecules/micrograms of total RNA in the glomeruli. The type B receptor (ANPRB) mRNA was present in smaller numbers (4.5-4.9 x 10(6) molecules/micrograms of total RNA) evenly throughout the kidney fractions. In situ hybridization demonstrated both ANPRA and ANPRC mRNA selectively in the glomerular epithelial cells and ANPRA mRNA in the collecting duct cells of the inner medulla. ANPRC was also localized on the foot processes of glomerular epithelial cells by immunohistochemistry using a specific antibody against the receptor. These results indicate that ANPRA is the major biologically active receptor for the ANP family of hormones in the kidney and is present selectively on the glomerular epithelial cells and inner medullary collecting duct cells. These cells are presumed to play a role in the regulation of glomerular filtration rate and sodium excretion induced by the family of ANP.

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Nucleotides regulate NaCl transport in mIMCD-K2 cells via P2X and P2Y purinergic receptors

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.4.f552 ◽

1999 ◽

Vol 277 (4) ◽

pp. F552-F559 ◽

Cited By ~ 37

Author(s):

David E. McCoy ◽

Amanda L. Taylor ◽

Brian A. Kudlow ◽

Katherine Karlson ◽

Margaret J. Slattery ◽

...

Keyword(s):

Plasma Membrane ◽

Apical Membrane ◽

Collecting Duct ◽

Short Circuit ◽

Short Circuit Current ◽

Extracellular Nucleotides ◽

P2x Receptor ◽

Apical Plasma Membrane ◽

Receptor Subtypes ◽

Nacl Transport

Extracellular nucleotides regulate NaCl transport in some epithelia. However, the effects of nucleotide agonists on NaCl transport in the renal inner medullary collecting duct (IMCD) are not known. The objective of this study was to determine whether ATP and related nucleotides regulate NaCl transport across mouse IMCD cell line (mIMCD-K2) epithelial monolayers and, if so, via what purinergic receptor subtypes. ATP and UTP inhibited Na+ absorption [measured via Na+ short-circuit current[Formula: see text])] and stimulated Cl− secretion [measured via Cl−short-circuit current ([Formula: see text])]. Using selective P2 agonists, we report that P2X and P2Y purinoceptors regulate [Formula: see text] and[Formula: see text]. By RT-PCR, two P2X receptor channels (P2X3, P2X4) and two P2Y G protein-coupled receptors (P2Y1, P2Y2) were identified. Functional localization of P2 purinoceptors suggest that [Formula: see text] is stimulated by apical membrane-resident P2Y purinoceptors and P2X receptor channels, whereas[Formula: see text] is inhibited by apical membrane-resident P2Y purinoceptors and P2X receptor channels. Together, we conclude that nucleotide agonists inhibit[Formula: see text] across mIMCD-K2 monolayers through interactions with P2X and P2Y purinoceptors expressed on the apical plasma membrane, whereas extracellular nucleotides stimulate [Formula: see text]through interactions with P2X and P2Y purinoceptors expressed on the apical plasma membrane.

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Enhancement of renal concentrating ability in the dog by urea and related compounds

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1963.205.1.112 ◽

1963 ◽

Vol 205 (1) ◽

pp. 112-116 ◽

Cited By ~ 13

Author(s):

Lawrence Rabinowitz ◽

Ralph H. Kellogg

Keyword(s):

Collecting Duct ◽

Molecular Size ◽

Urine Osmolality ◽

Acute Administration ◽

Membrane Permeation ◽

Specific Chemical ◽

Solute Excretion ◽

Chemical Groups ◽

Related Compounds ◽

Unique Ability

Experiments were performed on vasopressin-infused dogs to test the effect on renal concentrating ability of acute administration of urea and seven other organic nonelectrolytes. In each experiment a control assessment of concentrating ability was obtained during administration of mannitol. This was followed by administration of a test compound in an amount designed to maintain the previous rate of solute excretion. When compared to control values, urine osmolality was significantly higher during administration of urea, methylurea, acetamide, 1,2-propanediol and 1,3-dimethylurea, but not during administration of thiourea, glycerol, or hexamethylenetetramine. Others have suggested that the enhancement of concentrating ability by urea is related to the unique ability of urea to diffuse through the collecting-duct membranes. In the present study, there appeared to be no simple correspondence between the degree to which urine osmolality increased and the physical properties generally recognized to affect membrane permeation: oil:water partition coefficient, molecular size, or specific chemical groups.

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Functional characterization of basolateral and luminal dopamine receptors in rabbit CCD

AJP Renal Physiology ◽

10.1152/ajprenal.2001.281.1.f114 ◽

2001 ◽

Vol 281 (1) ◽

pp. F114-F122 ◽

Cited By ~ 16

Author(s):

Osamu Saito ◽

Yasuhiro Ando ◽

Eiji Kusano ◽

Yasushi Asano

Keyword(s):

Receptor Agonist ◽

Collecting Duct ◽

Functional Characterization ◽

Receptor Subtypes ◽

Cortical Collecting Duct ◽

Basolateral Side ◽

Skf 81297 ◽

Transepithelial Voltage ◽

Specific Antagonist

Previous studies reported the existence of both D1- and D2-like receptors in the cortical collecting duct (CCD). However, especially with regard to natriuresis, it remains controversial. In the present study, rabbit CCD was perfused to characterize the receptor subtypes responsible for the tubular actions. Basolateral dopamine (DA) induced a dose-dependent depolarization of transepithelial voltage. Basolateral domperidone, a D2-like receptor antagonist, abolished depolarization, whereas SKF-81297, a D1-like receptor agonist, showed no significant change. In addition, bromocriptine, a D2-like receptor agonist, also caused depolarization, whereas SKF-81297, a D1-like receptor agonist, did not depolarize significantly. Moreover, RBI-257, a D4-specific antagonist, reversed the basolateral DA-induced depolarization. In contrast to the basolateral side, luminal DA caused depolarization via a D1-like receptor; however the change was less than that for basolateral DA. For further evaluation, 22Na+ flux ( J Na) was measured to confirm the effect of DA on Na+ transport. Basolateral DA also caused a suppression of J Na, and this reaction was abolished by domperidone. These results suggested that the basolateral D2-like receptor is mainly responsible for the natriuretic action of DA in rabbit CCD.

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