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【关键词】 protein
Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas
ABSTRACT
Dopamine D1A receptor function is impaired in obesity-induced insulin resistance, contributing to sodium retention. We showed previously that uncoupling of D1A receptors from G proteins is responsible for diminished natriuretic response to dopamine in obese Zucker rats (OZRs). We hypothesized that overexpression of G protein-coupled receptor kinases (GRKs) leads to increased phosphorylation of D1A receptors, which in turn causes uncoupling of the receptors from Gs proteins in proximal tubules of OZRs. We also examined effects of an insulin sensitizer, rosiglitazone, in correcting these defects. We found that basal and agonist (fenoldopam)-induced coupling of D1A receptors to Gs proteins was impaired in proximal tubules of OZRs compared with lean Zucker rats (LZRs). Moreover, basal serine phosphorylation of D1A receptors was elevated two- to threefold in proximal tubules of OZRs compared with LZRs. Fenoldopam increased D1A receptor phosphorylation in proximal tubules of LZRs but not OZRs. Compared with that in LZRs, GRK4 expression in OZRs was elevated 200300% in proximal tubule cell lysates and GRK2 expression was 30% higher in plasma membranes isolated from proximal tubules of OZRs. Rosiglitazone treatment restored basal and agonist-induced coupling of D1A receptors to Gs proteins and reduced basal serine phosphorylation of D1A receptors, GRK4 expression, and translocation of GRK2 to the plasma membrane in proximal tubules of OZRs. Furthermore, rosiglitazone significantly reduced fasting blood glucose and plasma insulin in OZRs. Collectively, these results suggest that insulin resistance is responsible for GRK4 overexpression and GRK2 translocation leading to hyperphosphorylation of D1A receptors and their uncoupling from Gs proteins as rosiglitazone treatment corrects these defects in OZRs.
dopamine; D1A receptors; hyperphosphorylation; G protein-coupled receptors; kidney; obesity
INSULIN RESISTANCE IN HUMANS is linked to several cardiovascular complications, including hypertension (1, 11, 33). Hypertension in insulin-resistant patients and animal models is reported to be a result of sodium retention caused by failure of the kidneys to regulate sodium excretion (7, 27, 30). It is well established that dopamine, a natriuretic hormone locally synthesized in renal proximal tubules, is essential for maintenance of sodium homeostasis (16, 21). Under conditions of high salt intake, there is an increase in synthesis of dopamine, which increases sodium excretion by inhibition of sodium reabsorption across the nephron, mainly in the proximal tubules (13). Numerous studies have shown that renal dopamine function is impaired in obese, insulin-resistant humans (23, 34). Along the same lines, we have reported that natriuretic response to exogenously infused dopamine D1-like receptor agonist, SKF-38393, is reduced in insulin-resistant obese Zucker rats (26). This impaired natriuretic response to SKF-38393 is caused by insulin resistance, because treatment of these animals with an insulin-sensitizing drug, rosiglitazone, restored the ability of SKF-38393 to increase sodium excretion in obese Zucker rats (37). However, the exact pathway contributing to this impaired response to dopamine and its analogs in obesity remains unclear.
Radioligand binding and [35S]guanosine 5'-O-(3-thiotriphosphate) (GTPS) binding experiments done in our laboratory indicate that the impairment in D1-like receptor function in obese Zucker rats may be due to decreased D1-like receptor binding sites and, perhaps more likely, to uncoupling of D1-like receptors from G proteins in the plasma membrane of renal proximal tubules (15, 39). Although the D1-like receptor subfamily includes D1A and D1B receptors, only the D1A receptors are implicated in the natriuretic response of dopamine and its importance in preventing genesis of hypertension (3). Moreover, in renal proximal tubules, these receptors couple to mainly Gs and Gq proteins among all the G proteins (16, 21). Because [35S]GTPS binding does not differentiate between different G proteins, it derives qualitative rather than quantitative results. This may be a reason for 1) a nonsignificant difference in basal coupling and 2) only a minor difference in agonist-induced coupling of D1A receptors to G proteins in obese vs. lean Zucker rats in our previous study (37). Therefore, in the first part of the study, we examined the potential defects in basal and agonist (fenoldopam)-induced coupling of D1A receptors specifically to Gs proteins in the proximal tubules of obese Zucker rats by performing coimmunoprecipitation experiments. Coupling of D1A receptors with Gq proteins could not be measured because these two proteins do not coimmunoprecipitate (41). Furthermore, we determined whether improvement in insulin sensitivity with rosiglitazone corrects this coupling defect of D1A receptors.
Uncoupling of several G protein-coupled receptors (GPCRs) from G proteins, due to hyperphosphorylation of GPCRs resulting from overexpression of GPCR kinases (GRKs) that phosphorylate the receptors, has been reported in various pathological conditions, such as heart failure and hypertension (2, 4, 8, 12, 22, 31, 35, 38, 40). It is possible that similar overexpression of GRKs resulting in hyperphosphorylation of D1A receptors contributes to impaired G protein coupling and defective signaling. Moreover, hyperphosphorylation of D1A receptors also would explain reduced binding sites of these receptors on the plasma membrane, because phosphorylated receptors are targeted for endocytosis (9). Therefore, in the second part of this study, we examined the underlying mechanisms of impaired D1A receptor-Gs protein coupling in proximal tubules of obese Zucker rats by determining serine phosphorylation of D1A receptors as well as expression of GRK isoforms. Even though the above-mentioned mechanism has been established in animal models of hypertension and aging (4, 8, 22, 31, 35, 38), conditions other than obesity, therapeutic remedy for this dysfunction in dopamine pathway has not been addressed. Hence, we also determined the effects of rosiglitazone treatment on hyper-serine phosphorylation of D1A receptors as well as on expression of GRK isoforms in the proximal tubules of the obese Zucker rats to establish whether improvement in insulin sensitivity will correct the defects in these pathways.
METHODS
Material
The following chemicals and materials were purchased from the source indicated: rabbit anti-rat D1A receptor polyclonal antibodies (Chemicon, Temecula, CA); horseradish peroxidase-conjugated anti-rabbit antibodies and chemiluminescence substrate (Alpha Diagnostics, San Antonio, TX); anti-mouse phosphoserine antibodies and rabbit anti-Gs polyclonal antibodies (Calbiochem, San Diego, CA); mouse anti-human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) polyclonal antibodies, mouse anti-human GRK2 monoclonal antibodies, mouse anti-human GRK4 monoclonal antibodies, horseradish peroxidase-conjugated anti-mouse antibodies, and protein A/G-agarose (Santa Cruz Biotechnology, Santa Cruz, CA); Immobilon P membrane (Millipore, Bedford, MA); X-ray films (Kodak, Rochester, NY); and rat insulin radioimmunoassay kit (Linco Research, St. Charles, MO). All other chemicals were purchased from Sigma (St. Louis, MO) and were of the highest grade available.
Animals and Drug Treatment
Male obese and lean rats (Charles River Laboratories, Wilmington, MA) were maintained in an animal care facility with a 12:12-h light-dark cycle and provided standard rat chow (Purina Mills, St. Louis, MO) and tap water ad libitum. Twenty-four obese and lean rats (910 wk old) were randomly assigned to either rosiglitazone maleate (3 mg?kg1?day1) treatment or vehicle (1% carboxymethylcellulose) groups (6 obese and 6 lean rats in each group). The four groups included 1) obese treated, 2) lean treated, 3) obese control, and 4) lean control rats. The animals were treated daily by oral gavage for 15 days. All experimental protocols were approved by the University of Houston Institutional Animal Care and Use Committee.
Blood Glucose and Plasma Insulin Analysis
Rats were fasted overnight and anesthetized with pentobarbital sodium (50100 mg/kg ip) (37). Blood (500 μl) was collected from the aorta after a midline abdominal incision (37). Blood glucose values were determined using the Accu-Chek Advantage glucose monitoring system. Plasma insulin levels were measured using a rat insulin radioimmunoassay kit.
Isolation of Proximal Tubules
After blood samples were collected, proximal tubules were prepared from kidney cortex by using the Ficoll gradient method as previously described (37). The enriched proximal tubules from each group of rats were suspended in modified Krebs-Henseleit buffer A (37) and were used for further analysis or preparation of plasma membrane.
Preparation of Plasma Membranes
Plasma membranes were prepared from the frozen-thawed proximal tubular lysate as described previously (37).
Coimmunoprecipitation-Immunoblotting to Detect Gs Subunit Coupled to D1A Receptors
Immunoprecipitation of D1A receptors. Proximal tubular cell lysates were first treated with either vehicle (distilled water) or fenoldopam (1 μmol/l) at 37°C for 15 min and then used for coimmunoprecipitation experiments with a previously described method (19). Samples 1) without the addition of D1A receptor antibodies and 2) without proximal tubular lysate but with D1A receptor antibodies served as negative controls in the experiments. No D1A receptor protein band was detected in these lanes.
Immunoblotting of Gs subunit. The immunoprecipitated samples were resolved using 10% SDS-PAGE, and the proteins were electrotransferred on Immobilon P membrane. Immunoblotting of Gs subunit was performed as described previously (25). The same Immobilon P membranes were stripped of the antibody complex with stripping buffer and were used for immunoblotting of D1A receptors as described previously (37). Band density of Gs subunits was normalized to band density of D1A receptors.
Immunoprecipitation-Immunoblotting to Detect Serine-Phosphorylated D1A Receptors
Immunoprecipitation of D1A receptors. Proximal tubules were treated with either vehicle (distilled water) or fenoldopam (1 μmol/l) at 37°C for 2530 min. After freeze-thaw, D1A receptors were immunoprecipitated from these proximal tubular cell lysates as described previously (4). Samples 1) without the addition of D1A receptor antibodies and 2) without proximal tubular lysate but with D1A receptor antibodies served as negative controls in the experiments. No D1A receptor protein band was detected in these lanes.
Immunoblotting of serine-phosphorylated D1A receptors. The immunoprecipitated samples (20 μl) were resolved using 10% SDS-PAGE, and the proteins were electrotransferred onto an Immobilon P membrane. Immunoblotting of serine-phosphorylated D1A receptors with the use of anti-phosphoserine antibodies was performed as previously described (4). Moreover, these immunoprecipitated samples were used for immunoblotting of D1A receptors as described previously (37). Band density of serine-phosphorylated D1A receptors was normalized to band density of D1A receptors.
Immunoblotting of GRK2 and GRK4
Proximal tubular cell lysates or plasma membranes were used to prepare loading samples containing SDS-Laemmli and bromphenol blue for immunoblotting. These loading samples (protein: 3040 μg of proximal tubular cell lysates and 10 μg of plasma membranes) were then resolved using 10% SDS-PAGE and electrophoretically blotted onto an Immobilon P membrane. The membrane blots were incubated with primary monoclonal mouse anti-GRK2 (1:125) and anti-GRK4 (1:250) antibodies followed by horseradish peroxidase-conjugated secondary antibodies (1:4,000). The bands were detected with chemiluminescence substrate on X-ray films and were densitometrically quantified using Scion Image software provided by NIH. The same Immobilon P membranes were also used for immunoblotting of GAPDH for normalization as described previously (10).
Data Analysis
Data are represented as means ± SE of the number (n) of experiments. The results were analyzed using either Student's unpaired t-test or one-way ANOVA followed by the Newman-Keuls multiple comparison test to assess the significance of differences between groups (lean and obese rats treated with either vehicle or rosiglitazone) as well as within groups. Statistical analysis was done using GraphPad Prism version 3.02 (GraphPad Software, San Diego, CA). Statistical significance was considered at P < 0.05.
RESULTS
Body Weight, Fasting Blood Glucose, and Plasma Insulin
Obese rats weighed significantly more than lean rats in both vehicle and rosiglitazone treatment groups (Table 1). Treatment with rosiglitazone (3 mg?kg1?day1 for 15 days) caused significant weight gain in obese rats but not in lean rats (Table 1). Rosiglitazone treatment normalized fasting blood glucose levels and significantly reduced plasma insulin levels in obese treated rats (Table 1). Fasting blood glucose and plasma insulin levels were not significantly different between lean control and lean treated rats. These results suggest that obese rats are insulin resistant and that rosiglitazone treatment improves insulin sensitivity in these animals.
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Rosiglitazone Treatment Restores Basal and Agonist-Induced Gs Protein Coupling of D1A Receptors in Proximal Tubules of Obese Rats
In proximal tubular cell lysates of vehicle-treated obese rats, fenoldopam did not increase immunoprecipitation of Gs with D1A receptors (Fig. 1A). However, there was an approximately threefold increase in coimmunoprecipitation of Gs subunit with D1A receptors after fenoldopam treatment of proximal tubules in the other three groups of rats (Fig. 1A). Moreover, the basal amount of Gs subunit immunoprecipitated with D1A receptors was significantly reduced in proximal tubules of obese rats compared with lean rats (Fig. 1A), indicating a reduction in D1A receptors in the high-affinity state in proximal tubules of obese rats. When obese rats were treated with rosiglitazone, this decrease in basal D1A-Gs interaction was restored to the same level seen in lean rats (Fig. 1A). Interestingly, rosiglitazone treatment significantly increased the amount of Gs coimmunoprecipitated with D1A receptors in both lean and obese Zucker rats (Fig. 1A). Dopamine D1A receptor protein density was not significantly different among all four groups of rats (Fig. 1B). Therefore, variation in immunoprecipitated D1A receptors was caused by limitation of experimental technique and was compensated by normalizing density of Gs subunit with that of D1A receptors.
Rosiglitazone Treatment of Obese Zucker Rats Corrects Hyper-Serine Phosphorylation of D1A Receptors in Proximal Tubules
In proximal tubules of vehicle-treated obese rats, basal serine phosphorylation of D1A receptors was two- to threefold higher compared with that of vehicle-treated lean rats (Fig. 2A). However, when obese rats were treated with rosiglitazone, basal serine phosphorylation of D1A receptors was reduced to the levels seen in lean rats (Fig. 2A). There was no significant difference in basal serine phosphorylation of D1A receptors in proximal tubules of vehicle- and rosiglitazone-treated lean rats (Fig. 2A). In addition, fenoldopam failed to further increase serine phosphorylation of D1A receptors in proximal tubules of vehicle-treated obese rats (Fig. 2B). However, in rosiglitazone-treated obese rats, there was a two- to threefold increase in serine phosphorylation of D1A receptors when proximal tubules were treated with fenoldopam (Fig. 2B). There was no significant difference in the percent increase in D1A receptor phosphorylation by fenoldopam in vehicle-treated lean, rosiglitazone-treated lean, and rosiglitazone-treated obese rats. These hyper-serine-phosphorylated D1A receptors in proximal tubular cell lysates mainly represented D1A receptors on the plasma membranes, because no detectable band for serine-phosphorylated D1A receptors was observed in cytoplasmic compartments of proximal tubules from these rats (data not shown).
Overexpression of GRK4 in Proximal Tubules of Obese Zucker Rats is Corrected by Rosiglitazone Treatment
There was a more than twofold increase in GRK4 expression in proximal tubular cell lysates of vehicle-treated obese rats compared with vehicle-treated lean rats (Fig. 3). When obese rats were treated with rosiglitazone, GRK4 expression in proximal tubular cell lysates was significantly reduced, although it was not completely normalized to the levels seen in lean rats (Fig. 3). In addition, GRK4 expression in proximal tubular lysates was not significantly different between vehicle- and rosiglitazone-treated lean rats (Fig. 3).
Translocation of GRK2 to Plasma Membrane in Proximal Tubules of Obese Zucker Rats is Corrected by Rosiglitazone Treatment
There was no significant difference in GRK2 expression in proximal tubular cell lysates among all four groups of animals (Fig. 4A). However, because GRK2 is located mainly in the cytosolic fraction, we wanted to determine whether GRK2 is translocated to the plasma membranes, which is a site for GRK2 action. We detected an 30% increase in GRK2 immunoreactivity in plasma membranes isolated from proximal tubules of vehicle-treated obese rats compared with vehicle-treated lean rats (Fig. 4B). Moreover, rosiglitazone treatment significantly reduced GRK2 protein density on the plasma membrane in proximal tubules of obese Zucker rats (Fig. 4B). GRK2 immunoreactivity on the plasma membrane was not affected by rosiglitazone treatment in lean Zucker rats (Fig. 4B).
DISCUSSION
Our results show that uncoupling of D1A receptors from Gs proteins coexists with hyper-serine phosphorylation of D1A receptors, overexpression of GRK4, and translocation of GRK2 to the plasma membrane. Furthermore, rosiglitazone, by improving insulin sensitivity, corrects overexpression of GRK4 and translocation of GRK2, reduces basal serine phosphorylation of D1A receptors, and thus restores Gs protein coupling of D1A receptors in proximal tubules of obese Zucker rats.
In our attempt to identify mechanisms leading to impaired D1A receptor signaling in obese Zucker rats, we have previously demonstrated that these defect(s) exist(s) at both the receptor and receptor-G protein level (15, 39). It is possible that hyperphosphorylation of D1A receptors causes both of these defects. It is well documented that hyperphosphorylated GPCRs are uncoupled from G proteins (9). Furthermore, these receptors are then targeted for endocytosis and subsequent degradation (9). This, again, would explain why there is a 50% reduction in the receptor binding density on the plasma membrane (15, 39).
To study the coupling between D1A receptors and Gs proteins, we performed coimmunoprecipitation experiments in which the ability of Gs to coimmunoprecipitate with D1A receptors was measured in renal proximal tubules isolated from four groups of rats. The basal coupling of D1A receptors to Gs proteins was reduced in the proximal tubules of obese compared with lean Zucker rats. This observation indicates a loss of D1A receptors in the high-affinity state that are precoupled to Gs proteins. In addition, fenoldopam-induced coupling of the D1A receptors to Gs proteins was decreased in obese Zucker rats compared with lean rats. Rosiglitazone treatment, which improved insulin sensitivity, restored basal as well as fenoldopam-induced coupling of D1A receptors to Gs proteins in proximal tubules of obese Zucker rats. Interestingly, rosiglitazone also increased basal Gs coupling of D1A receptors in proximal tubules of the insulin-sensitive lean rats, indicating that this effect of rosiglitazone may be independent of its insulin-sensitizing activity. Moreover, the increase in basal Gs coupling of D1A receptors by rosiglitazone treatment also was not caused by changes in the level of expression of Gs or Gq proteins, because rosiglitazone treatment did not alter the expression of these proteins in the proximal tubules of both lean and obese Zucker rats (unpublished observation). Restoration of fenoldopam-induced Gs protein coupling of D1A receptors by rosiglitazone was, however, selectively present in obese Zucker rats and not in lean rats. Therefore, the restoration of fenoldopam-induced coupling of D1A receptors to Gs proteins is the result of improved insulin sensitivity in obese Zucker rats. It is noteworthy that although dopamine D1A receptor also couple to Gq proteins, we could not evaluate this interaction using our experimental technique because these receptors do not coimmunoprecipitate with Gq proteins (41).
To explore the possible mechanisms of the defective D1A receptor-G protein coupling, we measured the basal serine phosphorylation of D1A receptors in obese and lean Zucker rats. It has been reported that increased phosphorylation at serine residues in D1A receptors is responsible for the attenuation of the natriuretic effects of dopamine in both spontaneously hypertensive rats (SHR) and old Fischer 344 rats (4, 31). The basal serine phosphorylation of D1A receptors was found to be higher in the proximal tubules of the obese Zucker rats compared with that in the lean rats. Unlike the lean rats, in proximal tubules of obese rats, fenoldopam failed to increase serine phosphorylation of D1A receptors because these receptors were already hyperphosphorylated. This hyper-serine phosphorylation of D1A receptors could explain the uncoupling of D1A receptors from the Gs proteins and subsequent failure of agonists to stimulate second messengers in proximal tubules of obese rats. It is relevant to note that D1 (analogous to rat D1A) receptors in the proximal tubular culture from essential hypertensive patients are hyper-serine phosphorylated (8, 31). Furthermore, the proximal tubular culture from these patients do not exhibit a fenoldopam-mediated increase in cAMP compared with proximal tubules from normotensive humans (31). Similarly, dopamine fails to increase cAMP in proximal tubules of obese Zucker rats (14). Therefore, it appears that an increase in the basal serine phosphorylation of D1A receptors in the proximal tubules of the insulin-resistant obese Zucker rats leads to their uncoupling from the Gs proteins and loss of activation of downstream signaling components in these tubules.
Uncoupling of several GPCRs from G proteins has been reported in various pathological conditions, such as heart failure and hypertension. This uncoupling is due to hyperphosphorylation of GPCRs resulting from overexpression of GRKs that phosphorylate the receptors (5). For example, in cardiomyocytes of patients and animals with heart failure, GRK2 expression is increased, which results in hyperphosphorylation of -adrenergic receptors, rendering the receptors incapable of coupling to G proteins and activating downstream pathways (2, 12, 40). Similarly, in proximal tubules of both SHR (35, 38) and old Fisher 344 rats (22), uncoupling of D1A receptors from the G proteins is associated with hyperphosphorylation of serine residues in the D1A receptors (4, 31). This hyper-serine phosphorylation of D1A receptors is caused by the overexpression of GRK4 in proximal tubules of SHR rats (8). In this study, we found that not only was the basal level of expression of GRK4 increased in proximal tubules of obese Zucker rats, but there also was a translocation of GRK2 to the proximal tubular plasma membranes in these animals. Although GRK overexpression and hyper-serine phosphorylation of D1A receptor coexist in the proximal tubules of the obese Zucker rats, we have not performed experiments to link these two phenomena. However, ample evidence in the literature supports the notion that increased GRK expression causes agonist-independent hyper-serine phosphorylation of D1A receptors in proximal tubules of the kidney (4, 8, 31).
One consistent finding of our study was that the insulin-sensitizing drug rosiglitazone restored D1A receptor-G protein coupling, decreased D1A receptor hyper-serine phosphorylation, and also decreased the overexpression of GRK isoforms selectively in the proximal tubules of obese Zucker rats and not the lean rats. The obese Zucker rat is an established model of insulin resistance syndrome, which is exhibited by symptoms like hyperglycemia, hyperinsulinemia, and hypertriglycemia. It is possible that these metabolic defects interfere with renal dopamine D1-like receptor function in obese Zucker rats. For instance, triglyceride-derived fatty acids are responsible for hyperactivation of PKC in obesity, which interferes with insulin signaling pathways (6, 17, 24, 32). Similar hyperactivation of PKC in the proximal tubules of the obese Zucker rats may activate cellular components such as GRKs, which may interfere with dopamine function. Treatment of the obese rats with rosiglitazone, by normalizing the metabolic abnormalities in these animals (18, 28, 29, 36), may simultaneously restore D1A receptor coupling and function in proximal tubules of obese Zucker rats.
In summary, we have established that D1A receptors are uncoupled from the Gs proteins in the proximal tubules of the obese Zucker rats in both basal as well as agonist-stimulated states. This uncoupling of D1A receptors from Gs protein may be due to hyperphosphorylation of these receptors, which in turn is caused by overexpression of GRK4 and translocation of GRK2 to the plasma membrane in the proximal tubules of the obese Zucker rats. Furthermore, all of these defects are secondary to insulin resistance syndrome, because they are corrected by rosiglitazone treatment of obese Zucker rats. Therefore, the renal dopamine receptor dysfunction in the proximal tubules of the obese Zucker rats is a consequence of insulin resistance-related uncoupling of D1A receptors from Gs proteins.
GRANTS
This project was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-58743.
ACKNOWLEDGMENTS
This study was conducted as part of a PhD dissertation submitted in partial fulfillment of the requirements for the designated degree at the University of Houston (M. Trivedi).
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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