CLINICAL PERSPECTIVE
WHAT IS NEW?
- Activation of dopamine D4 receptors directly inhibits Na+-K+-ATPase (NKA) activity in renal proximal tubules (RPT) cells from Wistar-Kyoto (WKY) rats but not spontaneously hypertensive rats (SHRs).
- The expression of total D4 receptors was higher in SHR RPT cells than that in WKY RPT cells. However, its expression in RPT plasma membranes from SHRs was lower than that from WKY rats.
- The NO/cGMP signaling pathway was involved in the D4 receptor-induced inhibition of NKA activity in RPT cells.
WHAT ARE THE CLINICAL IMPLICATIONS?
- Stimulation of renal dopamine D4 receptors decreases renal sodium transports to maintain sodium homeostasis and may regulate the blood pressure.
- An impaired inhibitory regulation of NKA activity by renal D4 receptors may be involved in the development of hypertension.
- Restoring D4 receptors expression in RPT plasma membranes may be a potential strategy to improve the renal functions of D4 receptors.
1. Introduction
Essential hypertension, a complex trait caused by genetic, epigenetic, and environmental factors and their intricate interactions, is one of the most common health risk factors worldwide.[1] The pathogenesis of hypertension is intricate. Many organs, including the kidney, macro- and microcirculation, and the heart, are involved in the regulation of blood pressure and pathophysiology of hypertension. Among them, the kidney is the vital organ most involved in modulating blood pressure.[2]
Hypertensive patients have elevated sodium transport in the kidney, including in renal proximal tubules (RPTs). Specifically, RPTs are responsible for about 70% of renal sodium reabsorption and play an important role in the modulation of sodium homeostasis.[3] RPTs regulate sodium reabsorption through ion cotransporters, including the sodium hydrogen exchanger type 3 (NHE3), sodium glucose cotransporter, sodium amino acid cotransporter, electrogenic sodium bicarbonate cotransporter (NBCe) type 2, located at the luminal/apical membrane, and NBCe type 1 and Na+-K+-ATPase (NKA) located at the basolateral membrane.[3–5]
Dopamine acts as an autocrine/paracrine substance in nonneural tissues including the kidney.[6–10] Dopamine receptors are divided into 2 subtypes: D1-like receptors (D1R and D5R) couple to stimulatory G protein GαS and stimulate adenylyl cyclase activity, whereas D2-like receptors (D2R, D3R, and D4R) couple to inhibitory G protein Gαi/Gαo and inhibit adenylyl cyclase activity. D2-like receptors, in concert with D1-like receptors, synergistically decrease the activities of NKA and other sodium transporters in different segments of renal tubules.[6–12] During conditions of normal and increased sodium load, D1- and D2-like receptors interact to enhance natriuresis in rats.[12,13] The D4 dopamine receptor (D4 receptor) is widely expressed in the kidney, including the proximal tubules.[8,9,14] Our previous studies found that activation of the D4 receptor decreases expression of angiotensin II type 1 receptor (AT1 receptor) and insulin receptor in RPTs from Wistar-Kyoto (WKY) rats.[15,16] However, the role of D4 receptors in RPTs is still unclear. We hypothesized that activation of D4 receptors directly inhibits NKA activity in RPT cells. Thus, we investigated the effect of D4 receptors on regulation of NKA activity in RPT cells and explored its underlying mechanism.
2. Materials and methods
2.1. Cell culture
Immortalized RPT cells from WKY rats and spontaneously hypertensive rats (SHRs) were cultured (80% confluence) at 37°C in 95% air and 5% CO2 atmosphere in DMEM/F-12 culture media, as previously described.[15–17] The cells were extracted in ice-cold lysis buffer and then stored at −70°C until use.
To determine the abundance of D4 receptors in the plasma membrane of RPT cells, plasma membrane proteins in RPT cells were isolated with a commercially available kit (Minuteâ„¢ Plasma Membrane Protein Isolation and Cell Fractionation Kit, Invent Biotechnologies, Inc., Plymouth, Minnesota, USA).
2.2. NKA activity assay
To determine the effect of D4 receptors on NKA activity, RPT cells from WKY rats were treated with various concentration (10−9 to 10−5 mol/L) of PD168077 (a D4 receptor agonist) for 15 min (n = 8).[15,16] To determine the specificity of PD168077, cells were also incubated with L745870 (10−6mol/L, D4 receptor antagonist) and PD168077 for 15 min (n = 6). The NKA activity of RPT cells was measured as described previously.[18,19] After washing with chilled phosphate-free buffer, the pellet (membrane fraction) was suspended in 500 μL of 10 mmol/L Tris-HCl and 1 mmol/L ethylene diamine tetraacetic acid (EDTA, pH 7.5) on ice. Reactions were initiated by adding Tris-ATP (4 mmol/L) and terminated after 15 min of incubation at 37°C by adding 50 μL of 50% trichloracetate. NKA activity was calculated as the difference between total and ouabain-insensitive ATPase activity, and was normalized by total cell protein content.
2.3. Detection of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) production
To determine the mechanism of PD168077-mediated regulation of NKA activity, RPT cells from WKY rats were treated with the NO synthase inhibitor NG-nitro-L-arginine-methyl ester (L-NAME) and/or PD168077 for 15 min (n = 6). The NO reaction products, nitrate and nitrite, were measured in the culture medium. Briefly, RPT cells were incubated with the D4 receptor agonist PD168077 (10−6 mol/L) for 15 min in culture dishes containing 2 mL Krebs solution. The Griess test was used to measure NO content in the supernatant of these cells according to the assay kit manufacturer’s instructions (Nanjing Jiancheng Bioengineering Institute, Jiangsu, China). Absorbance of nitrite was measured by Thermo Scientific Varioskan Flash (Thermo LabSystems, Inc., Philadelphia, Pennsylvania, USA) at 540 nm (n = 8).
Since cGMP is involved in NO signaling,[20,21] we also investigated the role of cGMP in the inhibitory effect of D4 receptors on NKA activity in RPT cells. WKY RPT cells were treated for 15 min with the soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (ODQ, 10−5mol/L) (n = 5).[21] The level of cGMP (n = 13) was measured by an enzyme-linked immunosorbent assay according to the manufacturer’s instructions (Abcam, Cambridge, UK) (n = 13).
2.4. Immunoblotting
We next compared the expression of D4 receptor in the RPT cells from WKY rats and SHRs. Total protein (50 µg) was separated by electrophoresis on 10% or 15% sodium dodecyl sulfate-polyacrylamide gels and transferred onto nitrocellulose membranes (Amersham Life Science, Arlington, Texas, USA). The blots were blocked overnight and then incubated with polyclonal rabbit anti-rat D4 receptor antibody (1:400; Bioss, Woburn, Massachusetts, USA) overnight at 4°C. The membranes were washed with phosphate buffer saline-tween and then incubated with infrared-labeled secondary antibody (donkey anti-rabbit IRDye 800, Li-Cor Biosciences, Lincoln, Nebraska, USA). The bound complex was determined using the Odyssey Infrared Imaging System (Li-Cor Biosciences, Lincoln, Nebraska, USA). The densities of bands were normalized against that of glyceraldehyde-3-phosphate dehydrogenase (n = 4) or NKA (n = 3).
2.5. Statistical analysis
The data are expressed as mean ± SEM. Comparisons within groups were performed with repeated measures analysis of variance (ANOVA) (or paired t tests when only 2 groups were compared), and comparisons among groups (or t tests when only 2 groups were compared) were made using one-way ANOVA. Duncan’s test was the post hoc test. A value of P < 0.05 was considered significant.
3. Results
3.1. Stimulation of D4 receptors inhibits NKA activity in WKY RPT cells
Stimulation of D4 receptors with PD168077 inhibited NKA activity in a concentration-dependent manner [Figure 1A]. The inhibitory effect was evident beginning at 10−7 mol/L. Moreover, we also found that D4 receptor stimulation inhibited NKA activity in a time-dependent manner, which was observed as early as 10 min after stimulation and was maintained for at least 30 min [Figure 1B]. Moreover, we also found that a D4 receptor antagonist L745870 (10−6 mol/L) by itself had no effect, but blocked the inhibition of NKA activity by PD168077 in WKY RPT cells [Figure 1C].
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Figure 1:: Effect of the D4 receptor agonist PD168077 on NKA activity in RPT cells from WKY rats. (A) Concentration-response curves of NKA activity in RPT cells from WKY rats treated with PD168077 (10−9 to 10−5 mol/L) for 15 minutes (n = 8, *P < 0.05 vs. control). (B) Time-course of NKA activity in WKY cells treated with PD168077 (10−6 mol/L) (n = 6, *P < 0.05 vs. Control). (C) Effect of the D4 receptor agonist, PD168077, and/or antagonist, L745870, on NKA activity in RPT cells from WKY rats. The cells were incubated with the indicated reagents (PD168077, 10−6 mol/L; L745870, 10−6 mol/L) for 15 minutes (n = 6, *P < 0.05 vs. others). NKA: Na+-K+-ATPase; RPT: Renal proximal tubul; WKY: Wistar-Kyoto.
3.2. Stimulation of D4 receptors increases NO levels in RPT cells
Treatment with 10−4 mol/L L-NAME, which by itself had no effect on NKA activity, eliminated the inhibitory effect of PD168077 on NKA activity [Figure 2A]. Furthermore, we also found that activation of D4 receptors with PD168077 increased NO levels in the culture medium [Figure 2B]. These results suggested that NO is involved in D4 receptor-mediated inhibition of NKA activity in RPT cells.
Figure 2:: Role of NO in the inhibition of NKA activity by the D4 receptor in RPT cells. (A) Effect of L-NAME, a NO synthase inhibitor, on D4 receptor-mediated inhibition of NKA activity in WKY RPT cells. RPT cells were treated with the indicated reagents (PD168077, 10−6 mol/L; L-NAME, 10−4 mol/L) for 15 minutes (n = 6, *P < 0.05 vs. control). Control indicates vehicle-treated. (B) Effect of PD168077, a D4 receptor agonist, on NO concentration in the culture medium of RPT cells. Cells were treated with 10−6 mol/L PD168077 for 15 minutes (n = 8, *P < 0.05 vs. control). Control indicates vehicle-treated. L-NAME: NG-nitro L-arginine-methyl ester; NKA: Na+-K+-ATPase; NO: Nitric oxide; RPT: Renal proximal tubule; WKY: Wistar-Kyoto.
3.3. Stimulation of D4 receptors increases cGMP levels in RPT cells
While ODQ had no effect on NKA activity, inhibition of cGMP production eliminated the inhibitory effect of D4 receptors on NKA activity [Figure 3A]. We also found that activation of D4 receptors with PD168077 increased cGMP levels in RPT cells [Figure 3B]. These results indicated that cGMP signaling, downstream of NO, is involved in D4 receptor-mediated inhibition of NKA activity in WKY RPT cells.
Figure 3:: Role of cGMP in D4 receptor-mediated inhibition of NKA activity in RPT cells. (A) Effect of the soluble guanylyl cyclase inhibitor, ODQ, on D4 receptor-mediated inhibition of NKA activity in WKY RPT cells. RPT cells were treated with the indicated reagents (PD168077, 10−6 mol/L; ODQ, 10−6 mol/L) for 15 minutes (n = 5, *P < 0.05 vs. control). Control indicates vehicle-treated. (B) Effect of the D4 receptor agonist, PD168077, on the cGMP concentration in RPT WKY cells. RPT cells were treated with 10−6 mol/L PD168077 for 15 minutes (n = 13, *P < 0.05 vs. control). Control indicates vehicle-treated. cGMP: Cyclic guanosine monophosphate; NKA: Na+-K+-ATPase; ODQ: 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one; RPT: Renal proximal tubul; WKY: Wistar-Kyoto.
3.4. D4 receptor function is impaired in RPT cells from SHRs
Although 10−6 mol/L PD168077 inhibited NKA activity in WKY RPT cells, it had no effect in SHR RPT cells [Figure 4A], and the same result was found using a range of concentrations of PD168077 [Figure 4B]. We also found that expression of D4 receptors was higher in SHR RPT cells than in WKY RPT cells [Figure 4C]. The higher expression of D4 receptors in SHR RPT cells may be a compensatory response to reduced D4 receptor function in RPT cells from the hypertensive rats. Because the abundance of receptors in the plasma membrane is important for receptor function, D4 receptor expression was also measured in the plasma membrane of RPT cells. D4 receptor expression was lower in RPT plasma membranes from SHRs than from WKY rats [Figure 4D], indicating that loss of function of renal D4 receptors in hypertension may at least in part be due to its reduced levels in the plasma membranes of RPT cells.
Figure 4:: Effect of the D4 receptor agonist PD168077 on NKA activity in RPT cells from SHRs. (A) Effect of PD168077 (10−6 mol/L), a D4 receptor agonist, on NKA activity in RPT cells from WKY and SHRs (n = 7, *P < 0.05 vs. control). Control indicates vehicle-treated. (B) Concentration-response relationship of NKA activity in SHR RPT cells, incubated with PD168077 (10−9–10−5 mol/L) for 15 minutes (n = 5). Control indicates vehicle-treated. (C) Expression of the D4 receptor in RPT cells from WKY and SHRs (n = 4, *P < 0.05 vs. WKY). (D) Expression of the D4 receptor in the plasma membrane in RPT cells from WKY and SHRs (n = 3, *P < 0.05 vs. WKY). NKA: Na+-K+-ATPase; RPT: Renal proximal tubule; SHR: Spontaneously hypertensive rat; WKY: Wistar-Kyoto.
4. Discussion
There were several novel observations in our study. We showed that PD168077, a D4 receptor agonist, inhibited NKA activity in WKY RPT cells, and this activity was mediated via the NO/cGMP signaling pathway. By contrast, the inhibitory effect of D4 receptors on NKA activity in RPT cells was not observed in SHRs. This impairment of D4 receptor action in SHRs may be related to its reduced levels in the plasma membrane, despite increased total cell expression.
Dopamine exerts its physiological effects by binding its receptors to regulate renal tubular sodium reabsorption and blood pressure.[6–11,20] Previous studies focused on the effects of the D1-like receptors, not the D2-like receptor subfamily, in dopamine-mediated regulation of renal function.[7,10,21–23] However, studies have also shown the importance of the D2-like receptors in the regulation of blood pressure.[24,25] Moreover, there is increasing evidence that the D4 receptor, a member of the D2-like receptor subfamily, plays an important role in the development of hypertension. For example, in the kidney, activation of D4 receptors reduces the levels of AT1 and insulin receptors in RPTs of WKY rats.[15,16] Activation of D4 receptors also inhibits expression of AT1 and insulin receptors in vascular smooth muscle cells, decreasing their proliferation and migration.[26,27] Furthermore, systolic and diastolic blood pressure are both elevated in D4 receptor-deficient mice, which may involve increased renal AT1 receptor expression.[28] These reports suggest that the D4 receptor plays a role in the modulation of blood pressure via its interactions with other receptors in the kidney and blood vessels. However, the role of renal D4 receptor activation in modulation of blood pressure is still unclear.
NKA, expressed at the basolateral membrane of renal tubule cells, provides the driving force for sodium transport across the renal tubular apical membrane into the renal tubule cell by increasing sodium transport across the basolateral membrane.[29,30] In the kidney, NKA activity is up-regulated by antinatriuretic hormones, such as angiotensin, and down-regulated by natriuretic hormones, such as dopamine.[6–11,14,20,30–32] Our previous studies and those of others have shown that activation of dopamine D1-like receptors (D1 and/or D5 receptors) inhibits NKA activity in RPT cells.[6–11,14,20,30–34] However, the role of D4 receptor activation in regulating renal NKA activity remains unclear. The present study showed that activation of D4 receptors in WKY RPT cells inhibits NKA activity in a dose- and time-dependent manner. The effect in RPT cells was specifically exerted on D4 receptors because the D4 receptor antagonist L745870 reversed the inhibitory effect of PD168077 on NKA activity. By contrast, in RPT cells from SHRs, the inhibitory effect of D4 receptor activation was absent, which may contribute to the increase in renal sodium reabsorption that causes elevated blood pressure in SHRs. However, the expression of D4 receptors in SHR RPT cells was higher than in RPT cells from WKY rats, which may be a compensatory mechanism for the absence of D4 receptor inhibition of kidney NKA activity in the presence of hypertension.
NO signaling is involved in the inhibition of NKA activity in the kidney and blood vessels. Stimulation of the angiotensin II receptor 2 (AT2 receptor) initiates its translocation to the RPT cell apical membrane and the cellular internalization of NHE3 and NKA, leading to natriuresis in a NO/cGMP-dependent manner.[35] The activity of NKA in the kidney is increased in leptin-treated rats via a decrease in NO/cGMP signaling, leading to enhancement of renal tubular sodium reabsorption and a decrease in sodium excretion.[36] In the RPTs of SHRs, high concentrations of Ang II increase NADPH oxidase activity, which impairs the NO system and causes persistent NKA activation.[37] An increase in NO signaling is in some cases associated with stimulation of D4 receptors. The D4 receptor agonist PD168077 protects against hyperglycemia-induced endothelial dysfunction via the phosphatidylinositol 3-kinase (PI3K)/eNOS pathway.[38] PIP3EA and PD168077, 2 selective D4 receptor agonists, act in the paraventricular nucleus to facilitate penile erection, which occurs concomitantly with an increase in NO production.[39] In this study, administration of L-NAME, a NO synthase inhibitor, or ODQ, a soluble guanylyl cyclase inhibitor, blocked PD168077 inhibition of NKA activity in WKY RPT cells. Both NO and cGMP levels increased after activation of D4 receptors by PD168077. These results suggest that NO/cGMP signaling participates in renal D4 receptor-induced inhibition of NKA activity. It should be noted that as mentioned above, the upstream-downstream relationship between NO and cGMP is well established in the regulation of many physiological functions, including natriuresis.[40,41]
NO/cGMP-mediated regulation of NKA activity may be organ-specific. Stimulation of NO/cGMP elevates NKA activity in rat skeletal muscles, porcine internal mammary arteries, and neonatal rat cardiomyocytes.[42–44] However, in bovine choroid plexus and rat renal proximal tubules, NO/cGMP inhibits NKA activity.[45–49] Further studies have shown that NO/cGMP inhibits the activity of NKA by serine phosphorylation of the NKA α1-subunit, causing its internalization.[50]
5. Conclusion
In summary, we have shown that stimulation of D4 receptors directly inhibits NKA activity in RPT cells from WKY rats but not SHRs. The aberrant D4 receptors in SHRs were expressed at higher levels in RPTs, which may be a compensatory mechanism for the absence of D4 receptor function in the presence of hypertension. The NO/cGMP signaling pathway was involved in the D4 receptor-induced inhibition of NKA activity [Figure 5]. An impaired inhibitory regulation of NKA activity by renal D4 receptors may be involved in the development of hypertension. Most previous reports on the effects of renal D4 receptors only relied on physiological and pharmacological agonists and antagonists. Thus, studies of D4 receptor knockout mice and RPT cells lacking or overexpressing D4 receptors are needed.
Figure 5:: Central Illustration for the effect of D4R on the regulation of Na+-K+-ATPase activity in RPT cells. cGMP: Cyclic guanosine monophosphate; D4R: D4 dopamine receptor; L-NAME: NG-nitro-L-arginine-methyl ester, NKA: Na+-K+-ATPase; NO: Nitric oxide; ODQ: 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one; RPT: Renal proximal tubul; SHR: Spontaneously hypertensive rat; WKY: Wistar-Kyoto.
Funding
This study was supported in part by grants from the National Key R&D Program of China (2018YFC1312700), the National Natural Science Foundation of China (831730043), the Program of Innovative Research Team of the National Natural Science Foundation (81721001), Program for Changjiang Scholars and Innovative Research Team in University (IRT1216), Key Research and Development Projects of Science and Technology Innovation of Social and People’s Livelihood in Chongqing City (cstc2018jscx-mszdX0024), and Clinical Medical Research Talent Training Program from The Third Military Medical University (2018XLC10I2) and by National Institutes of Health, USA (P01HL074940, DK039308, and DK119652).
Conflicts of interest
None.
Editor note: Pedro A. Jose and Chunyu Zeng are Editorial Board Members of Cardiology Discovery. The article was subject to the journal’s standard procedures, with peer review handled independently of these editors and their research groups.
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