Limits...
Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure.

Zhang Y, Cuevas S, Asico LD, Escano C, Yang Y, Pascua AM, Wang X, Jones JE, Grandy D, Eisner G, Jose PA, Armando I - PLoS ONE (2012)

Bottom Line: Genetic factors, including polymorphisms of the dopamine D(2) receptor gene (DRD2) are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood.Our results demonstrate that the impact of decreased D(2)R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension.Deficient renal D(2)R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2)R expression and function.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.

ABSTRACT
Renal dopamine receptors participate in the regulation of blood pressure. Genetic factors, including polymorphisms of the dopamine D(2) receptor gene (DRD2) are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood. Mice lacking Drd2 (D(2)-/-) have elevated blood pressure, increased renal expression of inflammatory factors, and renal injury. We tested the hypothesis that decreased dopamine D(2) receptor (D(2)R) function increases vulnerability to renal inflammation independently of blood pressure, is an immediate cause of renal injury, and contributes to the subsequent development of hypertension. In D(2)-/- mice, treatment with apocynin normalized blood pressure and decreased oxidative stress, but did not affect the expression of inflammatory factors. In mouse RPTCs Drd2 silencing increased the expression of TNFα and MCP-1, while treatment with a D(2)R agonist abolished the angiotensin II-induced increase in TNF-α and MCP-1. In uni-nephrectomized wild-type mice, selective Drd2 silencing by subcapsular infusion of Drd2 siRNA into the remaining kidney produced the same increase in renal cytokines/chemokines that occurs after Drd2 deletion, increased the expression of markers of renal injury, and increased blood pressure. Moreover, in mice with two intact kidneys, short-term Drd2 silencing in one kidney, leaving the other kidney undisturbed, induced inflammatory factors and markers of renal injury in the treated kidney without increasing blood pressure. Our results demonstrate that the impact of decreased D(2)R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension. Deficient renal D(2)R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2)R expression and function.

Show MeSH

Related in: MedlinePlus

Effect of apocynin on renal cortical expression of TNFα, MCP-1, and IL-6, and urinary excretion of IL-6. Expression of TNFα (25 kDa) and MCP-1 (17 kDa) protein in renal cortex was semi-quantified by immunoblotting. Inset shows one set of immunoblots. Results were corrected for expression of GAPDH and expressed as percentage of D2+/+ mice treated with vehicle, *P<0.05 vs. vehicle or apocynin treated D2+/+; n = 5/group. Renal expression, semi-quantified by immunoblotting (25 kDa), and urinary excretion of IL-6 quantified by ELISA in 24 h urine samples. Results are expressed as percentage of D2+/+ mice treated with vehicle. *P<0.05 vs. vehicle or apocynin treated D2+/+; n = 5/group.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3375266&req=5

pone-0038745-g003: Effect of apocynin on renal cortical expression of TNFα, MCP-1, and IL-6, and urinary excretion of IL-6. Expression of TNFα (25 kDa) and MCP-1 (17 kDa) protein in renal cortex was semi-quantified by immunoblotting. Inset shows one set of immunoblots. Results were corrected for expression of GAPDH and expressed as percentage of D2+/+ mice treated with vehicle, *P<0.05 vs. vehicle or apocynin treated D2+/+; n = 5/group. Renal expression, semi-quantified by immunoblotting (25 kDa), and urinary excretion of IL-6 quantified by ELISA in 24 h urine samples. Results are expressed as percentage of D2+/+ mice treated with vehicle. *P<0.05 vs. vehicle or apocynin treated D2+/+; n = 5/group.

Mentions: Treatment with apocynin decreased systolic blood pressure in D2−/− mice (vehicle: 121±5; apocynin: 96±2 mm Hg; n = 5; P<0.05) but not in D2+/+ mice (vehicle: 98±3; apocynin 95±5 mmHg; n = 5). Apocynin also decreased the urinary excretion of the oxidative stress marker 8-isoprostane in D2−/− mice (vehicle: 3166±456; apocynin: 1874±553 pg/mg creatinine; n = 5, P<0.04) to levels similar to those in wild-type mice (vehicle: 1344±365; apocynin: 1542±280 pg/mg creatinine; n = 5). Treatment with apocynin, however, did not normalize the expression of TNFα, MCP-1, or IL-6 in D2−/− mice. TNFα expression in renal cortex was higher in vehicle-treated D2−/− than vehicle- treated D2+/+ mice; apocynin had no effect on TNFα expression in D2+/+ or D2−/− mice. MCP-1 protein expression was also higher in vehicle-treated D2−/− than in vehicle-treated D2+/+ mice; apocynin had no effect on MCP-1 expression in D2+/+ mice but decreased it in D2−/− mice although not to the level observed in D2+/+ mice (Figure 3). Renal cortical IL-6 protein expression and urinary excretion of IL-6 were also higher in vehicle-treated D2−/− than in vehicle-treated D2+/+ mice; apocynin had no effect on IL-6 in D2+/+ mice but modestly decreased its levels in D2−/− mice although they remained higher than D2+/+ mice (Figure 3).


Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure.

Zhang Y, Cuevas S, Asico LD, Escano C, Yang Y, Pascua AM, Wang X, Jones JE, Grandy D, Eisner G, Jose PA, Armando I - PLoS ONE (2012)

Effect of apocynin on renal cortical expression of TNFα, MCP-1, and IL-6, and urinary excretion of IL-6. Expression of TNFα (25 kDa) and MCP-1 (17 kDa) protein in renal cortex was semi-quantified by immunoblotting. Inset shows one set of immunoblots. Results were corrected for expression of GAPDH and expressed as percentage of D2+/+ mice treated with vehicle, *P<0.05 vs. vehicle or apocynin treated D2+/+; n = 5/group. Renal expression, semi-quantified by immunoblotting (25 kDa), and urinary excretion of IL-6 quantified by ELISA in 24 h urine samples. Results are expressed as percentage of D2+/+ mice treated with vehicle. *P<0.05 vs. vehicle or apocynin treated D2+/+; n = 5/group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375266&req=5

pone-0038745-g003: Effect of apocynin on renal cortical expression of TNFα, MCP-1, and IL-6, and urinary excretion of IL-6. Expression of TNFα (25 kDa) and MCP-1 (17 kDa) protein in renal cortex was semi-quantified by immunoblotting. Inset shows one set of immunoblots. Results were corrected for expression of GAPDH and expressed as percentage of D2+/+ mice treated with vehicle, *P<0.05 vs. vehicle or apocynin treated D2+/+; n = 5/group. Renal expression, semi-quantified by immunoblotting (25 kDa), and urinary excretion of IL-6 quantified by ELISA in 24 h urine samples. Results are expressed as percentage of D2+/+ mice treated with vehicle. *P<0.05 vs. vehicle or apocynin treated D2+/+; n = 5/group.
Mentions: Treatment with apocynin decreased systolic blood pressure in D2−/− mice (vehicle: 121±5; apocynin: 96±2 mm Hg; n = 5; P<0.05) but not in D2+/+ mice (vehicle: 98±3; apocynin 95±5 mmHg; n = 5). Apocynin also decreased the urinary excretion of the oxidative stress marker 8-isoprostane in D2−/− mice (vehicle: 3166±456; apocynin: 1874±553 pg/mg creatinine; n = 5, P<0.04) to levels similar to those in wild-type mice (vehicle: 1344±365; apocynin: 1542±280 pg/mg creatinine; n = 5). Treatment with apocynin, however, did not normalize the expression of TNFα, MCP-1, or IL-6 in D2−/− mice. TNFα expression in renal cortex was higher in vehicle-treated D2−/− than vehicle- treated D2+/+ mice; apocynin had no effect on TNFα expression in D2+/+ or D2−/− mice. MCP-1 protein expression was also higher in vehicle-treated D2−/− than in vehicle-treated D2+/+ mice; apocynin had no effect on MCP-1 expression in D2+/+ mice but decreased it in D2−/− mice although not to the level observed in D2+/+ mice (Figure 3). Renal cortical IL-6 protein expression and urinary excretion of IL-6 were also higher in vehicle-treated D2−/− than in vehicle-treated D2+/+ mice; apocynin had no effect on IL-6 in D2+/+ mice but modestly decreased its levels in D2−/− mice although they remained higher than D2+/+ mice (Figure 3).

Bottom Line: Genetic factors, including polymorphisms of the dopamine D(2) receptor gene (DRD2) are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood.Our results demonstrate that the impact of decreased D(2)R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension.Deficient renal D(2)R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2)R expression and function.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.

ABSTRACT
Renal dopamine receptors participate in the regulation of blood pressure. Genetic factors, including polymorphisms of the dopamine D(2) receptor gene (DRD2) are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood. Mice lacking Drd2 (D(2)-/-) have elevated blood pressure, increased renal expression of inflammatory factors, and renal injury. We tested the hypothesis that decreased dopamine D(2) receptor (D(2)R) function increases vulnerability to renal inflammation independently of blood pressure, is an immediate cause of renal injury, and contributes to the subsequent development of hypertension. In D(2)-/- mice, treatment with apocynin normalized blood pressure and decreased oxidative stress, but did not affect the expression of inflammatory factors. In mouse RPTCs Drd2 silencing increased the expression of TNFα and MCP-1, while treatment with a D(2)R agonist abolished the angiotensin II-induced increase in TNF-α and MCP-1. In uni-nephrectomized wild-type mice, selective Drd2 silencing by subcapsular infusion of Drd2 siRNA into the remaining kidney produced the same increase in renal cytokines/chemokines that occurs after Drd2 deletion, increased the expression of markers of renal injury, and increased blood pressure. Moreover, in mice with two intact kidneys, short-term Drd2 silencing in one kidney, leaving the other kidney undisturbed, induced inflammatory factors and markers of renal injury in the treated kidney without increasing blood pressure. Our results demonstrate that the impact of decreased D(2)R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension. Deficient renal D(2)R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2)R expression and function.

Show MeSH
Related in: MedlinePlus