Effects of long-term ouabain treatment on blood pressure, sodium excretion, and renal dopamine D1 receptor levels in rats

Evidence to date suggests that a positive interaction between natriuretic factors promotes sodium excretion to maintain sodium homeostasis and blood pressure. Although the involvement of renal dopamine D1 receptor (D1R) in promoting sodium excretion is well established; the role of Angiotensin (Ang) 1-7 Mas receptor (MasR) is not clear. Here we provide evidence for a functional interaction between these two renal G protein-coupled receptors which suggests that natriuretic response to Ang 1-7 via MasR is dependent on D1R activation. Male Sprague Dawley rats of comparable weight and age were infused with Ang 1-7, MasR antagonist DPro, D1R agonist SKF38393 and D1R antagonist SCH23390. Blood pressure was monitored throughout the experimental procedure and none of the infused drugs affected the pressure. Animals infused with saline alone served as controls. Infusion of Ang1-7 caused significant natriuresis and robust diuresis compared to saline. SKF38393 infusion also induced significant natriuresis and diuresis when compared to saline infusion. Both natriuretic and diuretic response to Ang 1-7 was blocked by Dpro and SCH23390. However, Dpro failed to block SKF38393 response. Concomitant infusion of SKF38393 and Ang 1-7 did not show a cumulative natriuretic or diuretic effect when compared to SKF38393 or Ang 1-7 infusion alone. FENa (%), control (saline): 0.30 ± 0.09; Ang 1-7: 1.03 ± 0.21; Ang 1-7 plus Dpro: 0.49 ± 0.11; Ang 1-7 plus SCH23390: 0.36 ± 0.10; SKF38393: 0.83 ± 0.16; SKF38393 plus SCH23390: 0.41 ± 0.09; SKF38393 plus Dpro: 0.82 ± 0.17; Ang 1-7 plus SKF38393: 1.06 ± 0.21. These data suggest that Ang 1-7 via MasR causes natriuresis which is dependent on D1R activation. On the other hand, renal D1R-mediated sodium excretion is independent of MasR. This study is a paradigm shift as these data identify a novel functional unidirectional interaction between renal MasR and D1R which deviates from commonly known receptor-receptor interaction.

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In Utero Exposure to Fine Particulate Matter Causes Hypertension Due to Impaired Renal Dopamine D1 Receptor in Offspring

Cellular Physiology and Biochemistry ◽

10.1159/000488418 ◽

2018 ◽

Vol 46 (1) ◽

pp. 148-159 ◽

Cited By ~ 7

Author(s):

Zhengmeng Ye ◽

Xi Lu ◽

Yi Deng ◽

Xinquan Wang ◽

Shuo Zheng ◽

...

Keyword(s):

Blood Pressure ◽

Particulate Matter ◽

Sodium Excretion ◽

Fine Particulate Matter ◽

In Utero ◽

D1 Receptor ◽

In Utero Exposure ◽

Fine Particulate ◽

Pm2.5 Exposure ◽

Renal Dopamine

Background/Aims: Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particulate matter (PM2.5) exposure in utero causes hypertension in the offspring, but the exact mechanisms are not clear. Renal dopamine D1 receptor (D1R), regulated by G protein-coupled receptor kinase type 4 (GRK4), plays an important role in the regulation of renal sodium transport and blood pressure. In this present study, we determined if renal D1R dysfunction is involved in PM2.5–induced hypertension in the offspring. Methods: Pregnant Sprague–Dawley rats were given an oropharyngeal drip of PM2.5 (1.0 mg/kg) at gestation day 8, 10, and 12. The blood pressure, 24-hour sodium excretion, and urine volume were measured in the offspring. The expression levels of GRK4 and D1R were determined by immunoblotting. The phosphorylation of D1R was investigated using immunoprecipitation. Plasma malondialdehyde and superoxide dismutase levels were also measured in the offspring. Results: As compared with saline-treated dams, offspring of PM2.5-treated dams had increased blood pressure, impaired sodium excretion, and reduced D1R-mediated natriuresis and diuresis, accompanied by decreased renal D1R expression and GRK4 expression. The impaired renal D1R function and increased GRK4 expression could be caused by increased reactive oxidative stress (ROS) induced by PM2.5 exposure. Administration of tempol, a redox-cycling nitroxide, for 4 weeks in the offspring of PM2.5-treated dam normalized the decreased renal D1R expression and increased renal D1R phosphorylation and GRK4 expression. Furthermore, tempol normalized the increased renal expression of c-Myc, a transcription factor that regulates GRK4 expression. Conclusions: In utero exposure to PM2.5 increases ROS and GRK4 expression, impairs D1R-mediated sodium excretion, and increases blood pressure in the offspring. These studies suggest that normalization of D1R function may be a target for the prevention and treatment of the hypertension in offspring of mothers exposed to PM2.5 during pregnancy.

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Inflammation compromises renal dopamine D1 receptor function in rats

AJP Renal Physiology ◽

10.1152/ajprenal.00366.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. F1543-F1549 ◽

Cited By ~ 15

Author(s):

Mohammad Asghar ◽

Gaurav Chugh ◽

Mustafa F. Lokhandwala

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Antioxidant Enzyme ◽

Salt Intake ◽

Primary Cultures ◽

Dopamine D1 Receptor ◽

D1 Receptor ◽

High Salt ◽

High Salt Intake ◽

Renal Dopamine

We tested the effects of inflammation on renal dopamine D1 receptor signaling cascade, a key pathway that maintains sodium homeostasis and blood pressure during increased salt intake. Inflammation was produced by administering lipopolysaccharide (LPS; 4 mg/kg ip) to rats provided without (normal salt) and with 1% NaCl in drinking water for 2 wk (high salt). Control rats had saline injection and received tap water. We found that LPS increased the levels of inflammatory cytokines, interleukin-6, and tumor necrosis factor-α in the rats given either normal- or high-salt intake. Also, these rats had higher levels of oxidative stress markers, malondialdehyde and nitrotyrosine, and lower levels of antioxidant enzyme superoxide dismutase in the renal proximal tubules (RPTs). The nuclear levels of transcription factors NF-κB increased and Nrf2 decreased in the RPTs in response to LPS in rats given normal and high salt. Furthermore, D1 receptor numbers, D1 receptor proteins, and D1 receptor agonist (SKF38393)-mediated 35S-GTPγS binding decreased in the RPTs in these rats. The basal activities of Na-K-ATPase in the RPTs were similar in control and LPS-treated rats given normal and high salt. SKF38393 caused inhibition of Na-K-ATPase activity in the primary cultures of RPTs treated with vehicle but not in the cultures treated with LPS. Furthermore, LPS caused an increase in blood pressure in the rats given high salt but not in the rats given normal salt. These results suggest that LPS differentially regulates NF-κB and Nrf2, produces inflammation, decreases antioxidant enzyme, increases oxidative stress, and causes D1 receptor dysfunction in the RPTs. The LPS-induced dysfunction of renal D1 receptors alters salt handling and causes hypertension in rats during salt overload.

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Glycaemic control with insulin prevents the reduced renal dopamine D1 receptor expression and function in streptozotocin-induced diabetes

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfq150 ◽

2010 ◽

Vol 25 (9) ◽

pp. 2945-2953 ◽

Cited By ~ 15

Author(s):

M. Moreira-Rodrigues ◽

J. Quelhas-Santos ◽

P. Serrao ◽

C. Fernandes-Cerqueira ◽

B. Sampaio-Maia ◽

...

Keyword(s):

Glycaemic Control ◽

Dopamine D1 Receptor ◽

D1 Receptor ◽

Receptor Expression ◽

Streptozotocin Induced Diabetes ◽

Renal Dopamine ◽

And Function

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A6612 In Utero Exposure to Fine Particulate Matter Causes Hypertension Due to Impaired Renal Dopamine D1 Receptor in Offspring

Journal of Hypertension ◽

10.1097/01.hjh.0000548178.30586.fc ◽

2018 ◽

Vol 36 ◽

pp. e47

Author(s):

Lu Xi ◽

Chunyu Zeng

Keyword(s):

Particulate Matter ◽

Fine Particulate Matter ◽

In Utero ◽

Dopamine D1 Receptor ◽

D1 Receptor ◽

In Utero Exposure ◽

Fine Particulate ◽

Renal Dopamine

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Long-term exercise attenuates blood pressure responsiveness and modulates kidney angiotensin II signalling and urinary sodium excretion in SHR

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320311408750 ◽

2011 ◽

Vol 12 (4) ◽

pp. 394-403 ◽

Cited By ~ 22

Author(s):

Silmara Ciampone ◽

Rafael Borges ◽

Ize P de Lima ◽

Flávia F Mesquita ◽

Elizabeth C Cambiucci ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Exercise Training ◽

Sodium Excretion ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

Receptor Expression ◽

Spontaneously Hypertensive ◽

Wistar Kyoto

Observations have been made regarding the effects of long-term exercise training on blood pressure, renal sodium handling and renal renin–angiotensin–aldosterone (RAS) intracellular pathways in conscious, trained Okamoto–Aoki spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKy) normotensive rats, compared with appropriate age-matched sedentary SHR and WKy. To evaluate the influence of exercise training on renal function and RAS, receptors and intracellular angiotensin II (AngII) pathway compounds were used respectively, and lithium clearance and western blot methods were utilised. The current study demonstrated that increased blood pressure in SHR was blunted and significantly reduced by long-term swim training between the ages of 6 and 16 weeks. Additionally, the investigators observed an increased fractional urinary sodium excretion in trained SHR (SHRT) rats, compared with sedentary SHR (SHRS), despite a significantly decreased creatinine clearance (CCr). Furthermore, immunoblotting analysis demonstrated a decreased expression of AT1R in the entire kidney of TSHR rats, compared with SSHR. Conversely, the expression of the AT2R, in both sedentary and trained SHR, was unchanged. The present study may indicate that, in the kidney, long-term exercise exerts a modulating effect on AngII receptor expression. In fact, the present study indicates an association of increasing natriuresis, reciprocal changes in renal AngII receptors and intracellular pathway proteins with the fall in blood pressure levels observed in TSHR rats compared with age-matched SSHR rats.

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Reduced renal dopamine D1 receptor function in streptozotocin-induced diabetic rats

AJP Renal Physiology ◽

10.1152/ajprenal.00227.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. F451-F457 ◽

Cited By ~ 39

Author(s):

Aditi Marwaha ◽

Anees Ahmad Banday ◽

Mustafa F. Lokhandwala

Keyword(s):

Atpase Activity ◽

Sodium Excretion ◽

Type I Diabetes ◽

Receptor Activation ◽

Diabetic Rats ◽

D1 Receptor ◽

Skf 38393 ◽

Receptor Expression ◽

Type I ◽

Renal Dopamine

Dopamine, via activation of renal D1 receptors, inhibits the activities of Na-K-ATPase and Na/H exchanger and subsequently increases sodium excretion. Decreased renal dopamine production and sodium excretion are associated with type I diabetes. However, it is not known whether the response to D1 receptor activation is altered in type I diabetes. The present study was designed to examine the effect of streptozotocin-induced type I diabetes on renal D1 receptor expression and function. Streptozotocin treatment of Sprague-Dawley rats caused a fourfold increase in plasma levels of glucose along with a significant decrease in insulin levels compared with control rats. Intravenous administration of SKF-38393, a D1 receptor agonist, caused a threefold increase in sodium excretion in control rats. However, SKF-38393 failed to produce natriuresis in diabetic rats. SKF-38393 caused a concentration-dependent inhibition of Na-K-ATPase activity in renal proximal tubules of control rats. However, the ability of SKF-38393 to inhibit Na-K-ATPase activity was markedly diminished in diabetic rats. D1 receptor numbers and protein abundance as determined by [3H]SCH-23390 ligand binding and Western blot analysis were markedly reduced in diabetic rats compared with control rats. Moreover, SKF-38393 failed to stimulate GTPγS binding in proximal tubular membranes from diabetic rats compared with control rats. We conclude that the natriuretic response to D1 receptor activation is reduced in type I diabetes as a result of a decrease in D1 receptor expression and defective receptor G protein coupling. These abnormalities may contribute to the sodium retention associated with type I diabetes.

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