(Hypertension. 1999;33:504-510.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Selective Inhibition of the Renal Dopamine Subtype D1A Receptor Induces Antinatriuresis in Conscious Rats
From the Departments of Medicine (Z.Q.W., R.M.C.) and Pathology (R.A.F.), University of Virginia Health Sciences Center, Charlottesville, Va.
Correspondence to Dr Robert M. Carey, Box 395, University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail RMC4C{at}virginia.edu
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Abstract—Both dopamine D1-like (D1A and D1B) and D2-like (D2, D3, and D4) receptor subfamilies are present in the kidney. Blockade of the intrarenal D1-like receptor family is associated with natriuresis and diuresis. Because the D1A and D1B receptor subtypes are not distinguishable by currently available dopaminergic agents, their functional role remains undefined. In the present study, the effect of selective inhibition of the renal D1A receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) was investigated in conscious uninephrectomized rats. After renal interstitial administration of Texas red–labeled D1A receptor AS-ODN, intense fluorescent signal was localized in the renal tubular epithelium and vasculature. In rats on normal salt intake, AS-ODN injected interstitially into the kidney reduced daily urinary sodium excretion (1.4±0.04 versus 0.8±0.2 mEq/d, n=5, P<0.05) and urine output (16.9±3.8 versus 12.5±3.6 mL/d, n=5, P<0.05). In rats on high sodium intake, continuous renal interstitial administration of D1A receptor AS-ODN transiently decreased daily urinary sodium excretion (5.4±0.5 versus 4.2±0.3 mEq/d, n=7, P<0.01) and urine output (27.6±4.5 versus 18.1±1.8 mL/d, n=7, P<0.01). Neither vehicle nor sense oligodeoxynucleotide had significant effects. Systolic blood pressure remained unchanged. The renal D1A receptor protein was significantly decreased by 35% and 46% at the end of the study in AS-ODN–treated rats on normal and high salt intake, respectively, whereas the D1B receptor and ß-actin were not affected. These results provide the first direct evidence that the renal D1A receptor subtype plays an important role in the control of sodium excretion.
Key Words: oligonucleotides, antisense • receptors, dopamine • kidney • sodium excretion
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Introduction |
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The renal dopaminergic system plays an important role in the regulation of blood pressure, sodium balance, and kidney function. Dopamine (DA), produced by the renal proximal tubule, acts as an intrarenal paracrine hormone mediating diuresis and natriuresis.1 2 3 Recent advances in molecular biology have provided the identification of at least 5 subtypes of DA receptors. These newly described DA receptors have been shown to correspond pharmacologically and biochemically to the classical D1-like (D1A and D1B in rodents, and D1 and D5 in humans) and D2-like (D2L, D2S, D3, and D4) receptor subfamilies on the basis of their ability to stimulate or inhibit adenylate cyclase, respectively.4 The expression of D1A, D1B, D2L, and D3 receptor subfamilies has been identified in the kidney.5 6 7 8 9 10 11 It is not clear whether these newly cloned DA receptor subtypes are functionally significant in DA-mediated renal responses. Pharmacological stimulation of D1-like receptor with D1-like receptor agonist is associated with natriuresis and diuresis by both renal hemodynamic and tubular mechanisms. Inhibition of D1-like receptor with D1-like receptor antagonists produces antinatriuresis and antidiuresis independently of hemodynamic changes.1 12 However, currently available dopaminergic agents fail to differentiate between the D1A and D1B receptor subtypes, and the role of specific D1-like receptor subtypes in D1-like receptor-mediated renal actions is yet to be determined.
Antisense oligodeoxynucleotide (AS-ODN) provides a novel strategy to inhibit the synthesis of a specific gene product.13 14 Because renal tubule epithelial cells, especially proximal tubule cells, can take up large quantities of oligodeoxynucleotide (ODN), the kidney appears to be an excellent target organ for a site-directed AS-ODN approach.15 16 In the present study, AS-ODN directed toward dopamine D1A receptor subtype mRNA was delivered directly into the renal interstitium to inhibit selectively the synthesis of the renal D1A receptor subtype, and the role of the renal D1A receptor subtype in the control of sodium excretion and blood pressure was evaluated in conscious uninephrectomized rats.
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Methods |
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Sprague-Dawley female rats (body weight, 200 to 240 g, Harlan Sprague Dawley Inc, Harlan Teklad, Madison, WI) were used. The rats were provided with free access to regular rat chow (0.28% NaCl, Bioserve) and tap water unless described otherwise. All experimental procedures on animals were approved by the University of Virginia School of Medicine Animal Care Committee.
Design and Synthesis of ODN
AS-ODN against rat D1A receptor mRNA and
its control, sense oligodeoxynucleotide (S-ODN), were
synthesized and purified with reverse-phase high-performance
liquid chromatography (GENSET SA) as 21-mer
phosphorothioate-modified ODNs (antisense: 5'-GGT AGA AGT GTT AGG AGC
CAT-3', sense: 5'-ATG GCT CCT AAC ACT TCT ACC-3'), from
nucleotides 60 to 80 of the rat D1A
receptor cDNA.17 The designed sequences showed no homology
with other known mammalian sequences deposited in the Genbank database
(GenBank accession no. M35077), as screened using the Blast
program.
Uninephrectomy and Renal Interstitial Catheter
Implantation
Under general anesthesia with
intraperitoneal injection of ketamine (60
mg/kg) and xylazine (4 mg/kg), the right kidney was removed. An
indwelling renal interstitial catheter, constructed using
an 8-mm piece of polyethylene tubing (PE-10, Clay Adams) connected by
Bipax epoxy resin glue (Tra-Con) to a 4-cm PE-60 tubing, was implanted
into the left kidney through a small hole made with a 26-gauge needle.
The catheter tip was placed at the cortex by insertion 2 to 3 mm
in depth from the outer edge of the kidney, and was anchored in place
on the kidney surface with Mersilene surgical mesh (Ethicon) and a
small piece of abdominal fat using Vetbond tissue adhesive (3M Animal
Care Products). Ten days were allowed for the left kidney to adapt
to right nephrectomy and for the rat to recover from the surgery.
Placement of the catheter tip was confirmed at the end of the
experiment by careful visual inspection. Rats with kidney damage were
excluded from the study.
Distribution of D1A Receptor AS-ODN in the Kidney
and Brain
Ten days after the right nephrectomy, the rats were
anesthetized, and the renal interstitial catheter
was implanted as described above and filled with Ringer's solution.
Three days later, 50 µL of Ringer's solution with or without Texas
red–conjugated AS-ODN (2 µg/µL, GENSET SA) (n=2/group) was
injected during a 10-minute period into the renal interstitium through
the implanted catheter. Twenty-four hours later, the kidney and brain
were collected with the rat under deep anesthesia. The
tissues were fixed with 2% paraformaldehyde and
cryprotected with 30% sucrose. The frozen sections were examined with
a fluorescence microscope.
Effect of D1A Receptor AS-ODN on Urinary Sodium
Excretion During Normal Salt Intake
Ten days after the right nephrectomy, the rats were
anesthetized, and the renal interstitial catheter
was implanted as described above and filled with Ringer's solution.
Three days later, 24-hour urine was collected as control. Then, 50 µL
of one of the following was infused into the renal interstitium during
a 10-minute period (n=5/group): AS-ODN (4 µg/µL) in Ringer's
solution; S-ODN (4 µg/µL) in Ringer's solution; or Ringer's
solution alone. Daily urine collection was continued for an additional
3 days. At the end of the study, the rat was deeply
anesthetized and the kidney was quickly removed, frozen in
liquid nitrogen, and stored at -70°C until protein extraction.
Effect of D1A Receptor AS-ODN on Urinary Sodium
Excretion and Systolic Blood Pressure During High Salt
Intake
After the uninephrectomy and renal
interstitial catheter implantation, renal
interstitial infusion of the Ringer's solution was
commenced through a microosmotic pump (model 2002, 0.5 µL/h, Alza)
connected to the other end of the catheter. The rats were provided with
regular rat chow and high salt drinking water (0.45% NaCl) ad libitum
throughout the study period. Ten days later, daily urine was collected
for 2 consecutive days. After systolic blood pressure was
measured by noninvasive tail-cuff method (Blood Pressure
Analyzer, model 179, IITC), the rats were anesthetized
again as above; 50 µL of one of the following was given into the
renal interstitium during a 10-minute period (n=7/group): AS-ODN (2
µg/µL) in Ringer's solution; S-ODN (2 µg/µL) in Ringer's
solution; or Ringer's solution alone, followed by a constant infusion
of given ODN (AS- or S-ODN, 4 µg/µL) or Ringer's solution alone
through a new microosmotic pump (model 1007D, 0.5 µL/h, Alza). One
day of postsurgery recovery was allowed before daily urine collection
was resumed. Blood pressure was measured again at days 2 and 5. At the
end of the study, the rat was deeply anesthetized and the
kidney from each animal was quickly removed, frozen in liquid nitrogen,
and stored at -70°C until protein extraction.
Western Blot Analysis
The specific polyclonal rat D1A
(directed against a peptide sequence
299GSEETQPFC307 on the
third extracellular domain) and D1B (directed
against a peptide sequence
266CRSRGAYEPDPSLR279 on the
third intracellular domain) receptor subtype antibodies used in the
present study have been well characterized.6 7 18 19 20
Western blotting was performed as previously described.18
Kidney protein samples (100 µg/rat) were electrophoretically
size-separated under denaturing conditions in 7.5%
SDS-polyacrylamide gels, followed by transfer of the
proteins onto nitrocellulose membranes. The blots were soaked overnight
at 4°C in Tris-buffered saline containing 5% nonfat dry milk and
0.1% polyoxyethylene sorbitan monolaurate (Tween 20). The membranes
were then probed for 2 hours with either polyclonal
D1A, D1B receptor antibody
or monoclonal ß-actin antibody (Sigma) (1:1000 dilution in
Tris-buffered saline with 5% nonfat dry milk and 0.1% Tween 20).
Blots were subsequently washed and incubated with peroxidase-conjugated
donkey anti-rabbit or sheep anti-mouse secondary antibody (1:2500
dilution, Amersham). The immunoreactive protein was detected with ECL
Western blotting detection kit (Amersham). Quantitative assessment of
band densities was performed by scanning densitometry (ImageQuant,
Molecular Dynamics). Membranes were stripped between incubations with
different antibodies in a Tris-buffered solution containing 2% SDS and
100 mmol/L ß-mercaptoethanol at 50°C.
Urinary sodium concentration was measured by flame photometry (IL943, Instrumentation Laboratory). Statistical analysis was performed with a Macintosh StatView program (Abacus Concepts). Data were expressed as mean±SE. Comparisons were made with analysis of variance, followed by Fisher's protected least significant difference test for multiple comparisons when appropriate. A P value <0.05 was considered statistically significant.
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Results |
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Distribution of AS-ODN Within the Kidney and Brain
Fluorescent signal (Texas red) was detected in the cortex and medulla of the whole kidney 24 hours after renal interstitial injection. Significant uptake of the AS-ODN occurred in both tubular epithelium and intrarenal vasculature with minimal signal present in the glomerulus (Figure 1
). No fluorescent signal was
observed in the brain (data not shown).
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Effect of AS-ODN on Urinary Sodium Excretion and Blood
Pressure
In rats on normal salt intake, D1A receptor
AS-ODN injected interstitially into the kidney
significantly reduced 24-hour urinary sodium excretion (1.4±0.04
versus 0.8±0.2 mEq/d, n=5, P<0.05) and urine output
(16.9±3.8 versus 12.5±3.6 mL/day, n=5, P<0.05) (Figure 2, left). Similarly, in rats maintained
on high sodium intake, continuous renal interstitial
administration of D1A receptor AS-ODN, but not
vehicle or S-ODN, decreased daily urinary sodium excretion (5.4±0.5
versus 4.2±0.3 mEq/d, n=7, P<0.01) and urine output
(27.6±4.5 versus 18.1±1.8 mL/day, n=7, P<0.01) (Figure 2, right). In both cases, daily urine output and sodium
excretion returned to control levels before the end of the study.
Neither Ringer's solution nor S-ODN had significant effects (Figure 2). Systolic blood pressure remained unchanged during
the study (Figure 3).
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Western Blot Analysis of Renal D1A and
D1B Receptor Subtypes and ß-Actin
Three days after renal interstitial injection of
D1A receptor AS-ODN to rats on normal salt
intake, renal D1A receptor subtype protein was
still significantly decreased by 35% compared with rats treated with
vehicle or S-ODN (Figure 4). In rats on
high salt balance, 5-day continuous renal interstitial
infusion of AS-ODN reduced renal D1A receptor
protein by 46% (Figure 5). However,
expression of the D1B receptor and ß-actin in
the kidney was not significantly altered (Figures 4 and 5).
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Discussion |
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AS-ODN strategy offers the potential to suppress selectively the expression of specific genes within somatic cells in the absence of confounding systemic variables as often seen in genetically engineered animals. Once entering the cells, AS-ODNs are thought to bind to their complementary region of the target mRNA and, by a number of mechanisms, selectively inhibit gene expression.13 14 Renal epithelial cells, especially proximal tubule cells, can effectively take up phosphorothioated ODN,21 22 23 24 and the renal tubule appears to be an excellent target for gene transfer into the kidney.15 16 The utility of this strategy has been demonstrated successfully by in vivo administration of AS-ODNs against neural and inducible isoforms of nitric oxide synthase, the angiotensin subtype 1 receptor, the Na+-Pi cotransporter, intercellular adhesion molecule-1, and transforming growth factor-ß1 in the kidney.25 26 27 28 29 30 31 In the present study, effective renal cellular uptake of AS-ODN was confirmed by distribution of Texas red–labeled ODN in renal tubular epithelium and vasculature 24 hours after renal interstitial injection.
In a recent review, Missale et al4 concluded that the physiological function of the newly cloned dopamine receptor subtypes is still unknown and remains a major challenge in the coming years. Acute blockade of the intrarenal D1-like receptor family with SCH 23390 induces significant decrease of urinary flow rate, sodium excretion, and fractional sodium excretion by tubular mechanisms.12 Both D1A and D1B receptor subtypes are expressed in the kidney.5 6 7 8 The D1A receptor subtype has been localized in the proximal and distal tubules, collecting ducts, and intrarenal arterioles and juxtaglomerular apparatus but not glomerulus.5 6 7 Whole body abrogation of the D1A receptor subtype has been found to cause abnormal behavioral function with increased locomotor activity or rearing behavior,32 33 and high blood pressure in D1A receptor null mice.34 However, the precise role of the renal D1A receptor subtype in control of sodium excretion and blood pressure has not been established.
Our research group has previously demonstrated that D1A receptor AS-ODN is able to block translation of the D1A receptor protein and the D1-like receptor agonist fenoldopam-stimulated phospholipase C expression in LTK- cells stably transfected with rat D1A receptor cDNA.35 It also prevents fenoldopam-induced cAMP accumulation and renin secretion in cultured rat juxtaglomerular cells.36 In the present study, we sought to use the same AS-ODN, complementary to D1A receptor mRNA, to elucidate the possible role of renal D1A receptors in regulation of urinary sodium excretion in conscious rats either on normal salt intake or during long-term salt loading, one of the most powerful stimuli known to activate the renal DA system. The need to target the renal tubular epithelium and vasculature (two major sites of the D1A receptor in the kidney), together with the poor ability of phosphorothioated ODN to penetrate the blood-brain barrier, offers particular advantages for AS-ODN strategy.
In the present study, renal interstitial administration of D1A receptor AS-ODN led to a significant decrease in renal D1A receptor protein, whereas expression of the renal D1B receptor and the structural protein ß–actin was not affected. Selective inhibition of the renal D1A receptor significantly reduced urinary sodium excretion in rats on either normal or high salt diet. Although the D1A receptor subtype protein in the whole kidney was significantly suppressed, the current findings do not allow us to determine whether hemodynamic or tubular mechanisms are involved or the relative importance of the tubular and vascular D1A receptor in the observed decrease in urinary sodium excretion. It is noteworthy, however, that antinatriuresis in the current study is short-lasting and is not accompanied by an increase in systolic blood pressure, despite the fact that renal D1A receptor protein was still significantly inhibited at the end of the experiment. In contrast, generalized loss (knockout) of the D1A receptor in D1A receptor null mice is associated with elevated blood pressure.34 In the present study, a possible compensatory increase in renal DA production may have counteracted the antinatriuretic effect engendered by AS-ODN-induced decrease (knockdown) in renal D1A receptor. As activation of D1A receptors stimulates renin secretion from juxtaglomerular cells,36 a decrease in renin secretion (and thereby, intrarenal angiotensin II or circulating aldosterone) in antisense-treated rats may have limited the antinatriuretic effect caused by the decrease in renal D1A receptor. Activation of other compensatory factors in response to decreased urinary sodium excretion may also be involved. More complete or longer term suppression of the renal D1A receptor may be necessary to induce sustained antinatriuresis or hypertension.
In summary, our data demonstrate that renal interstitial administration of the D1A receptor AS-ODN selectively suppressed renal D1A receptor subtype expression and produced significant antidiuresis and antinatriuresis in conscious uninephrectomized rats. These results suggest that the renal D1A receptor subtype plays an important role in the short-term control of sodium excretion.
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Acknowledgments |
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This work was supported in part by grant R01-HL-59948 (R.M.C.) from the National Institutes of Health. We are grateful to Dr Marjorie A. Ariano (Department of Neuroscience, Flinch University of Health Science/The Chicago Medical School, Chicago, IL) for providing rat D1B receptor antibody, and to Nancy L. Howell for technical assistance.
Received September 16, 1998; first decision October 13, 1998; accepted October 23, 1998.
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X.-H. Jin, H. E. McGrath, J. J. Gildea, H. M. Siragy, R. A. Felder, and R. M. Carey Renal Interstitial Guanosine Cyclic 3', 5'-Monophosphate Mediates Pressure-Natriuresis Via Protein Kinase G Hypertension, May 1, 2004; 43(5): 1133 - 1139. [Abstract] [Full Text] [PDF]
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 J. M. Stern, J. Chen, R. B. Silver, D. P. Poppas, E. D. Vaughan Jr., and D. Felsen Effect of UUO on D1aR expression reveals a link among dopamine, transforming growth factor-{beta}, and nitric oxide Am J Physiol Renal Physiol, March 1, 2004; 286(3): F509 - F515. [Abstract] [Full Text]
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P. M. Abadir, R. M. Carey, and H. M. Siragy Angiotensin AT2 Receptors Directly Stimulate Renal Nitric Oxide in Bradykinin B2-Receptor-Null Mice Hypertension, October 1, 2003; 42(4): 600 - 604. [Abstract] [Full Text] [PDF]
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R. M. Carey Renal Dopamine System: Paracrine Regulator of Sodium Homeostasis and Blood Pressure Hypertension, September 1, 2001; 38(3): 297 - 302. [Abstract] [Full Text] [PDF]
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X.-H. Jin, H. M. Siragy, and R. M. Carey Renal Interstitial cGMP Mediates Natriuresis by Direct Tubule Mechanism Hypertension, September 1, 2001; 38(3): 309 - 316. [Abstract] [Full Text] [PDF]
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A.-P. Zou, H. Billington, N. Su, and A. W. Cowley Jr Expression and Actions of Heme Oxygenase in the Renal Medulla of Rats Hypertension, January 1, 2000; 35(1): 342 - 347. [Abstract] [Full Text] [PDF]
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