Urea transporter UT-A1 and aquaporin-2 proteins decrease in response to angioten - 《American Journal of Physiology》美国生理学杂志干细胞之家



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作者：Janet D. Klein, Brian P. Murrell, Suzanne Tucker, Young-Hee Kim, and Jeff M. Sands作者单位：Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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      【摘要】$ a; `. y3 O/ e' w! Z( Z9 t/ d6 w
   The kidney responds to high levels of ANG II, as may occur during malignant hypertension, by increasing sodium and water excretion. To study whether kidney medullary transporters contribute to this response, rats were made hypertensive using ANG II. Within 3 days of being given ANG II, systolic blood pressure (BP) was increased (200 mmHg), vs control (130 mmHg), and remained high through day 14. Kidney inner medullary (IM) tip and base and outer medulla were analyzed for transporter protein abundance. There were significant decreases in UT-A1 urea transporter, aquaporin-2 (AQP2) water channel, and NKCC2/BSC1 Na -K -2Cl - cotransporter. To determine whether the decreases were a response to hypertension, ANG II, or an ANG II-induced increase in aldosterone, rats were given 1 ) norepinephrine (to increase BP) and 2 ) ANG II plus spironolactone (to block the mineralocorticoid receptor). Norepinephrine (7 days) increased BP, urine volume, sodium excretion, and decreased urine osmolality and UT-A1, AQP2, and NKCC2/BSC1 abundances, similar to ANG II. ANG II alone or with spironolactone yielded similar increases in BP, urine volume, and urine osmolality, and decreases in UT-A1 and AQP2 proteins in the IM tip. Plasma vasopressin was unaffected by treatment. Water diuresis did not change UT-A1 but decreased AQP2 and NKCC2/BSC1 abundances. We conclude that decreases in UT-A1, AQP2, and NKCC2/BSC1 proteins may contribute to the diuresis and natriuresis that occur following ANG II or norepinephrine-induced acute hypertension and do not appear to involve ANG II stimulation of aldosterone or thirst.
      【关键词】 transporter aquaporin proteins decrease response angiotensin norepinephrineinduced hypertension
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IN RESPONSE TO VERY HIGH levels of ANG II, as may occur during malignant hypertension, the kidney attempts to increase sodium and water excretion ( 3, 12, 16 ). In the renal medulla, if the key transport proteins involved in the urine concentrating mechanism were downregulated in response to malignant hypertension, their downregulation would contribute to a diuresis and natriuresis. Specifically, the UT-A1 urea transporter and the NKCC2/BSC1 Na -K -2Cl - cotransporter are the major proteins responsible for reabsorbing the solutes (urea and NaCl) that contribute to the generation of a hypertonic renal medulla, and the aquaporin-2 (AQP2) water channel is the major protein regulating the permeability of the collecting duct to water (reviewed in Refs. 10, 15, 19 ). Downregulation of NKCC2/BSC1, similar to administering furosemide, would lead to a natriuresis. A diuresis would result from either a decrease in the medullary osmotic gradient due to downregulation of NKCC2/BSC1 and/or UT-A1, or from downregulation of AQP2.
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In this study, we sought to test the effect of severe acute hypertension due to administration of high doses of ANG II on these medullary transport proteins. We previously showed that aldosterone itself causes a decrease in UT-A1 protein abundance ( 2 ). To determine whether any effect of ANG II was due to its stimulation of aldosterone, we also made rats hypertensive by administering norepinephrine, which raises blood pressure but does not increase ANG II or serum aldosterone. Finally, we made rats hypertensive with ANG II but pretreated these rats with the mineralocorticoid receptor antagonist spironolactone. We found that following ANG II or norepinephrine-induced hypertension, UT-A1, AQP2, and NKCC2/BSC1 proteins were downregulated, and that these changes did not involve aldosterone.

METHODS
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Animal preparation. All animal protocols were approved by the Emory University Institutional Animal Care and Use Committee. Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA), weighing 200-250 g, received free access to water and standard rat chow (Purina) containing 23% protein. Blood pressure was measured by tail cuff using a Visitech (Apex, NC) blood pressure-monitoring system. Rats received ANG II (0.75 mg·kg -1 ·day -1 ) or norepinephrine (2.74 mg·kg -1 ·day -1 ) via mini-pump (Alzet/Durect, Palo Alto, CA). In one experiment, spironolactone was given in addition to ANG II. Spironolactone (100 mg) was suspended in olive oil (1 ml); rats were injected subcutaneously with 0.1 mg·kg -1 ·day -1 ( 2 ). Rats were "trained" to be at ease in the monitoring platform for 3-5 consecutive days before any chemical manipulation. After the initial treatment, blood pressure was monitored every other day until the animals were killed by decapitation. ANG II was given for 7 or 14 days. Norepinephrine was given for 7 days. Spironolactone was given 3 days before the ANG II pump implantation and continued throughout the ANG II treatment. An additional group of rats was made water diuretic by giving them free access to 10% glucose water ( 7 ).1 E9 F- V+ l1 r

Sample preparation. Following death, rat kidneys were dissected into inner medullary tip and base and outer medulla. Tissue was placed into ice-cold isolation buffer (10 mmol/l triethanolamine, 250 mmol/l sucrose, pH 7.6, 1 µg/ml leupeptin, and 2 mg/ml PMSF), homogenized, then SDS was added to a final concentration of 1% for Western analysis of the total cell lysate (5-7). Total protein in each sample was measured by a modified Lowry method (Bio-Rad DC protein assay reagent, Bio-Rad, Richmond, CA). Urine was collected for measurement of urine urea nitrogen concentration and osmolality (Wescor vapor pressure osmometer, Logan, UT) determinations. Plasma was collected for assessment of vasopressin (Assay Designs, Ann Arbor, MI) and aldosterone (DPC, Los Angeles, CA) levels, and plasma osmolality (vapor pressure osmometer, Wescor).1 x1 n2 ]9 W3 q6 T! o" ^$ x5 O7 F
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Western analysis. Western analysis was performed as previously described ( 1, 4, 8, 9, 13 ). Briefly, rat inner medullary tissue was homogenized in ice-cold isolation buffer and brought to 1% SDS for Western analysis of total cell lysate ( 8, 13, 22 ). Proteins were size-separated by SDS-PAGE on Laemmli gels, electroblotted to PVDF membranes, and incubated with primary antibody overnight at 4°C. After being washed, the blot was incubated with fluorescently labeled secondary antibody and visualized with the LICOR IR imaging scanner. Parallel gels were stained with Coomassie blue to verify uniformity of gel loading. Laser densitometry was used to quantify the intensity of the resulting bands on western blot.
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Immunohistochemistry. Kidneys from ANG II-treated rats were preserved by in vivo perfusion with 4% paraformaldehyde (PFA) in live, isofluorane-anesthetized rats. After perfusing with fixative for 5-7 min, kidneys were removed and transverse thick slices (2-3 mm) were placed in the 4% PFA overnight at 4°C. Tissues were then placed in histology cassettes and washed successively with fresh 4% PFA (2 h, 4°C), PBS (3 x 10 min), 50 mmol/l NH 4 Cl/PBS (1 h), PBS (3 x 10 min), 70, 96, and 98% ethanol (EtOH; 2 h each), and xylene (overnight). Tissues were transferred to pure paraffin at 56°C for 2 h and then were embedded in paraffin.

Tissues were sliced to 2-µm thickness on a microtome and mounted on glass slides. After removing paraffin with xylene, endogenous peroxidase activity was blocked with 0.35% H 2 O 2 in methanol for 30 min. Target retrieval was accomplished by microwaving samples with 10 mmol/l Tris and 0.5 mmol/l EGTA (TEG) buffer. To prevent nonspecific antibody binding, sections were further blocked with 50 mmol/l NH 4 Cl in PBS (30 min) followed by 3 x 10-min incubation with 1% BSA, 0.2% gelatin, 0.05% saponin in PBS. Tissues were incubated with primary antibody, anti-UT-A1 (1:4,000 dilution) in 0.1% BSA, 0.3% Triton X-100 in PBS overnight at 4°C in a humidified chamber, then incubated with horseradish peroxidase-labeled secondary goat anti-rabbit IgG (DAKO, Carpinteria, CA) in the BSA/Triton diluent. Positive staining was visualized using a diaminobenzidine dye (brown). Cell nuclei were also counterstained with hematoxylin (blue).  K0 P( u8 @/ v& t5 @- k% K

Statistics. All data are presented as means ± SE. To test for statistical significance between two groups, we used a Student?s t -test. To test more than two groups, we used an ANOVA, followed by Tukey?s protected t -test ( 20 ) to determine which groups are significantly different. The criterion for statistical significance is P ) d+ M4 @; q. t4 x! r3 q& j
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RESULTS

ANG II. The systolic blood pressures of the normal rats averaged 121 ± 5 mmHg. Treatment of the rats with ANG II (65 ng·min -1 ·kg -1 body wt) for 14 days, delivered by osmotic mini-pump, did not increase blood pressure in all rats. There was no significant difference in kidney transporters between control rats and rats infused with ANG II at this dosage.
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Within 3 days of administration of 500 ng·min -1 ·kg -1 of ANG II, however, blood pressure was increased to an average of 185 ± 12 mmHg in all treated rats ( Fig. 1 ). Pair-fed control rats had similar changes in body wt through day 14 of the ANG II treatment (data not shown). When the kidneys of these animals were assessed for transporter abundances, there was a significant decrease in UT-A1 in both the tip (41%) and base (41%) portions of the inner medulla ( Fig. 2 ). Significant changes were also observed in AQP2 protein abundance in the same tissue samples, with a 76% decrease in AQP2 in the inner medulla tip and a 56% decrease in the inner medulla base ( Fig. 3 ). The NKCC2/BSC1 cotransporter protein abundance was also significantly reduced by 63% in the outer medulla from the ANG II-treated rats relative to controls ( Fig. 3 ). The reduced UT-A1 protein is clearly visible in the histochemical view of the ANG II-treated rat ( Fig. 4, top right ) relative to the control tissue ( Fig. 4, top left ). The change in UT-A1 is also visible in the reduced staining of the inner medullary collecting ducts shown in Fig. 4, bottom. Accompanying these changes in transporter abundances were increases in urine volume and sodium excretion ( Fig. 5 ).

Fig. 1. Blood pressure in ANG II-treated vs. control rats. Following a 3-day training period to accustom the rats to the blood pressure apparatus, blood pressures were determined in both control (solid line) and ANG II-treated rats (dotted line). ANG II pumps were implanted on day 0. Systolic blood pressure was increased within the first 3 days. Error bars indicate SE with n = 8-10 rats per group. * P

Fig. 2. UT-A1 in inner medullary (IM) tip and base of rats infused with ANG II for 14 days. Left : representative Western blots showing 3 animals per group of a total of n = 10 animals per group. Right : bar graph provides the densitometry from all animals provided as means ± SE. * P 6 k* f! t' W9 `) }+ j

Fig. 3. Aquaporin-2 (AQP2) in IM and Na -K -2Cl - cotransporter (NKCC2) in outer medulla (OM) of rats infused with ANG II for 14 days. Left : representative Western blots showing 3 animals per group of a total of n = 10 (for AQP2) or n = 11 (NKCC2) animals per group. Right : bar graphs provide the densitometry from all animals provided as means ± SE. * P 3 |+ ]5 |7 s  M6 h8 c8 G# }

Fig. 4. Immunohistochemistry of UT-A1 in kidney from control and ANG II-treated rats. Kidneys were prepared as described in METHODS. Brown color indicates positive antibody identification of protein. Top : x 10 magnification. Bottom : x 63 magnification.
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Fig. 5. Sodium excretion and urine volumes were increased in rats treated with ANG II for 14 days. Bars represent means ± SE; n = 4 animals per group. * P

Norepinephrine. To determine whether the elevated blood pressure was responsible for the changes in these transporters or whether the changes were a response to elevated aldosterone levels, blood pressure was raised using norepinephrine (1.9 µg·min -1 ·kg -1 body wt) instead of ANG II. A 7-day treatment with norepinephrine resulted in a significant increase in blood pressure (from 127 ± 5 to 171 ± 5; Fig. 6 ). A 7-day treatment was used for this protocol because the rats were not able to tolerate a longer treatment. Treatment with ANG II for 7 days resulted in responses in both blood pressure ( Fig. 6 ) and transporter abundances ( Figs. 7 and 8 ) that were comparable to the 14-day ANG II treatment. Although the change in blood pressure by norepinephrine was not as extensive as that resulting from ANG II, there were, nevertheless, significant decreases in UT-A1 in the inner medulla tip (62%) and base (34%; Fig. 7 ) and in AQP2 in the inner medulla tip (30%) and base (39%; Fig. 8 ). NKCC2/BSC1 was significantly decreased 24% in the outer medulla of norepinephrine-treated rats relative to control levels ( Fig. 8 ). Aldosterone levels were increased in the rats treated with ANG II for either 7 or 14 days, as opposed to those receiving norepinephrine for 7 days ( Fig. 9 A ). Despite the difference in aldosterone levels, both treatments (ANG II or norepinephrine) resulted in a reduced urine osmolality ( Fig. 9 B ). There was no significant difference in plasma osmolality between control and ANG II- or norepinephrine-treated rats (data not shown).: ~+ `' a+ C6 k" m
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Fig. 6. Blood pressure in norepinephrine vs. ANG II vs. control rats. Following a 3-day training period to accustom the rats to the blood pressure apparatus, blood pressures were determined in control (dotted line) and ANG II-treated rats (solid line) and norepinephrine-treated rats (dashed line). ANG II and norepinephrine pumps were implanted on day 0. Systolic blood pressure was increased within the first 3 days. Error bars indicate SE with n = 2-5 rats per group. * P
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Fig. 7. UT-A1 in IM tip and base of rats infused with ANG II or norepinephrine (Norepi) for 7 days. Left : representative Western blots showing 3 animals per group of a total of n = 5 animals per norepinephrine group. Two ANG II-treated animals were included in the study to show that the response at 7 days is essentially the same as that observed at 14 days. Right : bar graph provides the densitometry from all animals provided as means ± SE expressed as a percentage of control band density. * P
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Fig. 8. AQP2 in IM and NKCC2 in OM of rats infused with ANG II or Norepi for 7 days. Left : representative Western blots showing 3 animals per group of a total of n = 5 animals per Norepi group. Two ANG II-treated animals were included in the study to show that the response at 7 days is essentially the same as that observed at 14 days. Right : bar graph provides densitometry from all animals provided as means ± SE. * P
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Fig. 9. Serum aldosterone and urine osmolalities in rats infused with Norepi or ANG II for 7 or 14 days vs. control. * P   l9 w- x6 Q' x* F) w* ]6 R5 i* J" N

Spironolactone. To further prove that it was the ANG II-induced increase in blood pressure and not the change in aldosterone that was responsible for the altered abundances of UT-A1 and AQP2, rats were subjected to ANG II treatment (500 ng·min -1 ·kg -1 ) for 14 days with a parallel ANG II group that also received spironolactone (0.1 mg/kg) injected daily beginning 2 days before the onset of ANG II treatment. Blood pressures in ANG II-treated rats were elevated regardless of the presence of spironolactone ( Fig. 10 A ). In each case, the protein levels for UT-A1 or AQP2 in the rats receiving only ANG II were not statistically different from the ANG II rats that were also receiving spironolactone, and all ANG II rats showed UT-A1 and AQP2 levels that were statistically different from control rat levels ( Fig. 10 B ). There was no difference in plasma vasopressin levels between these three groups of rats ( Fig. 10 C ).
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Fig. 10. ANG II vs. ANG II sprionolactone (Spiro). A : blood pressures were determined in control (dotted line), ANG II-treated rats (dashed line), and ANG II-treated rats receiving daily injections of Spiro (solid line). Systolic blood pressure was increased within the first 4 days and remained statistically elevated relative to controls. Error bars indicate SE with n = 4-5 rats per group, * P

Hydration. In addition to increasing blood pressure, ANG II is a potent stimulator of thirst ( 21 ). To determine whether the changes in medullary transport proteins following ANG II administration could be due to ANG II-induced thirst resulting in polydipsia and polyuria, rats were made water diuretic for 7 days. There was no significant difference in UT-A1 protein abundance in the inner medulla tip between control and 7-day hydrated rats ( Fig. 11 ). In contrast, AQP2 protein was significantly decreased (43%) in the inner medulla tip and NKCC2/BSC1 protein was significantly decreased (21%) in the outer medulla.$ U+ q- q. B6 I  N

Fig. 11. Water diuresis for 7 days. Left : representative Western blots showing 3 animals per group of a total of 6 control and 6 water diuretic rats. UT-A1 and AQP2 are shown from the IM tip, and NKCC2/BSC1 from the OM. Right : bar graph provides the densitometry from all rats (means ± SE) as a percent of control band density. * P 2 ~4 g% C% u2 P* x

DISCUSSION3 @3 Y# |! ]+ d) R

The main finding in this study is that UT-A1, AQP2, and NKCC2/BSC1 protein abundances are decreased at 7-14 days of severe acute hypertension induced by infusing very high doses of ANG II or norepinephrine. Very high doses of ANG II may occur in malignant hypertension and may cause diuresis and natriuresis ( 3, 12, 16 ). The decreases in these transport proteins likely contribute to the diuresis and natriuresis in the rats.; K) X4 u1 I8 ^9 ~( x

Although the present study did not identify the mechanism for these changes, our findings tend to rule out two potential mechanisms: ANG II stimulated increases in aldosterone and thirst. An increase in aldosterone will result in extracellular fluid volume expansion, which has been shown to be accompanied by a decrease in UT-A1 and UT-A3 protein abundances ( 23 ). In that study, rats were given supplemental aldosterone for a maximum of 4 days and a high-salt diet to provoke volume expansion ( 23 ). Because we treated rats with ANG II for a minimum of 7 days, with no forced salt intake, we consider our model sufficiently different as to raise a question about whether aldosterone was mediating the decrease in UT-A1 abundance in our study. For this reason, we treated rats simultaneously with ANG II and spironolactone to block the mineralocorticoid receptor. The effect of spironolactone in the nonhypertensive rat is to reduce the abundances of the Na -Cl - cotransporter NCC, and alpha and gamma, but not beta ENaC ( 14 ). Although spironolactone had no effect on the abundance of UT-A1 in the adrenalectomized rat ( 2 ), its effect on UT-A1 in the normal rat has not been reported. In this study, blockage of the mineralocorticoid receptor with spironolactone did not affect the changes observed in the hypertensive ANG II-treated rats, suggesting that the decrease in UT-A1 was not due to an ANG II-induced increase in aldosterone levels. The verification that similar changes in transporter protein abundances occur when blood pressure is raised with norepinephrine also suggests that it is not aldosterone that is responsible for the decrease in UT-A1.

ANG II-mediated stimulation of thirst, resulting in polydipsia and polyuria, also does not appear to be involved, because 1 ) norepinephine causes similar changes in transport protein abundances but does not stimulate thirst ( 11, 17, 18, 21 ) and 2 ) plasma vasopressin levels are similar in control vs. ANG II-treated rats. As an additional control for the consequences of thirst, we made rats polyuric by water diuresis for 7 days. While both stimulation of thirst and water diuresis result in polyuria, water diuresis is not a perfect control for thirst as vasoprssin levels are likely to be reduced during water diuresis and the rats are not consuming water because they are thirsty. Regardless, we found that UT-A1 protein abundance was unchanged by water diuresis for 7 days. However, we cannot completely exclude a role for ANG II?s stimulation of thirst as contributing to the decreases in AQP2 and NKCC2/BSC1 protein abundances, as they were decreased in the 7-day water diuretic rats.

The decreases in UT-A1, AQP2, and NKCC2/BSC1 protein abundances appear to be in response to severe acute hypertension, regardless of whether it is induced by ANG II or norepinephrine. However, we cannot exclude the possibility that ANG II and norepinephrine have similar direct effects on UT-A1, AQP2, and NKCC2/BSC1 protein abundances. Also, although vasopressin was not different with the ANG II treatment, we cannot exclude the possibility that ANG II and norepinephrine elicit similar hemodynamic changes in the rats, such as volume expansion or increases in peripheral resistance or cardiac afterload, which could change the circulating levels of hormones that, in turn, result in the changes in UT-A1, AQP2, and NKCC2/BSC1 protein abundances that we measured. Thus future studies will be needed to further investigate the mechanisms for the changes in UT-A1, AQP2, and NKCC2/BSC1 protein abundances.
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In contrast to our findings, Dahl salt-sensitive hypertensive rats show no changes in NKCC2/BSC1 or AQP2 proteins, and both UT-A1 and UT-A3 proteins are upregulated, compared with the Dahl salt-resistant rats. In that study, the authors concluded that the increase in the urea transporters might contribute to the hypertension in the Dahl salt-sensitive rat model and that 11 -hydroxysteroid dehydrogenase type 2 might be involved in the increased abundance of the urea transporters. Thus the findings in the present study differ from those observed in the Dahl salt-sensitive rats. One possibility for the difference is that the present study examines the renal response to inducing severe acute hypertension by infusing high doses of ANG II or norepinephrine for 7-14 days, while the Dahl salt-sensitive rat is a genetic model of hypertension that has low plasma renin levels.% h- \' l) a  s
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This work was supported by National Institutes of Health Grants R01-DK-62081, R01-DK-41707, R01-DK-63657, and P01-DK-61521.

DISCLOSURES, K: H& f2 a# P2 K
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Portions of this work have been published in abstract form ( J Am Soc Nephrol 16: 133A, 2005).' l4 B! I5 W' }" D% \
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