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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.

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Effect of selective renal silencing of D2R in one kidney of mice without uni-nephrectomy on blood pressure and expression of inflammatory factors in the kidney and liver.Renal cortical D2R was silenced by the renal subcapsular infusion in the left kidney for seven days of Drd2 siRNA, via an osmotic minipump in adult male C57BL/6J mice (see Methods). A. Expression of D2R protein (55 kDa band) in renal cortex and liver was semi-quantified by immunoblotting. Results were corrected for GAPDH and expressed as % of NS siRNA treated kidneys. * P<0.05 vs non-silencing NS siRNA; n = 4/group. B. Systolic blood pressure measured under anesthesia in mice before and seven days after Drd2 siRNA infusion; n = 5/group. C. Renal cortical expression of TNFα, Ltα, NFkB1, MCP-1, MCP-2, IL-10, IL-11, osteopontin and collagen 1α1 mRNA was quantified by qRT-PCR, results corrected for expression of GAPDH mRNA, and expressed as fold change in comparison to their expression in mice treated with NS siRNA. *P<0.05 vs. NS; n = 5/group.
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pone-0038745-g006: Effect of selective renal silencing of D2R in one kidney of mice without uni-nephrectomy on blood pressure and expression of inflammatory factors in the kidney and liver.Renal cortical D2R was silenced by the renal subcapsular infusion in the left kidney for seven days of Drd2 siRNA, via an osmotic minipump in adult male C57BL/6J mice (see Methods). A. Expression of D2R protein (55 kDa band) in renal cortex and liver was semi-quantified by immunoblotting. Results were corrected for GAPDH and expressed as % of NS siRNA treated kidneys. * P<0.05 vs non-silencing NS siRNA; n = 4/group. B. Systolic blood pressure measured under anesthesia in mice before and seven days after Drd2 siRNA infusion; n = 5/group. C. Renal cortical expression of TNFα, Ltα, NFkB1, MCP-1, MCP-2, IL-10, IL-11, osteopontin and collagen 1α1 mRNA was quantified by qRT-PCR, results corrected for expression of GAPDH mRNA, and expressed as fold change in comparison to their expression in mice treated with NS siRNA. *P<0.05 vs. NS; n = 5/group.

Mentions: In order to eliminate the confounding effect of uni-nephrectomy and the increase in blood pressure in the above experiments, we also studied the effect of chronic unilateral renal subcapsular infusion of Drd2 siRNA in mice with two intact kidneys. Selective down-regulation of Drd2 in one kidney (Figure 6A) had no effect on systolic blood pressure (Figure 6B), suggesting that the intact kidney, in the short-term, is able to compensate for the effects of decreased Drd2 expression in the treated kidney. The mRNA expression of TNFα, Ltα, NFκB1, MCP-1 and MCP-2 was increased in the treated kidney to the same extent as in treated uni-nephrectomized mice; NFkB1 and IL-10 were increased but to a lesser extent than in uni-nephrectomized mice. The mRNA expression of IL-11 was similarly decreased. In contrast the expression of the injury markers osteopontin and Col 1α1 was increased to a greater extent than in infused remnant kidney of uni-nephrectomized mice (Figure 6C).


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 selective renal silencing of D2R in one kidney of mice without uni-nephrectomy on blood pressure and expression of inflammatory factors in the kidney and liver.Renal cortical D2R was silenced by the renal subcapsular infusion in the left kidney for seven days of Drd2 siRNA, via an osmotic minipump in adult male C57BL/6J mice (see Methods). A. Expression of D2R protein (55 kDa band) in renal cortex and liver was semi-quantified by immunoblotting. Results were corrected for GAPDH and expressed as % of NS siRNA treated kidneys. * P<0.05 vs non-silencing NS siRNA; n = 4/group. B. Systolic blood pressure measured under anesthesia in mice before and seven days after Drd2 siRNA infusion; n = 5/group. C. Renal cortical expression of TNFα, Ltα, NFkB1, MCP-1, MCP-2, IL-10, IL-11, osteopontin and collagen 1α1 mRNA was quantified by qRT-PCR, results corrected for expression of GAPDH mRNA, and expressed as fold change in comparison to their expression in mice treated with NS siRNA. *P<0.05 vs. NS; n = 5/group.
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getmorefigures.php?uid=PMC3375266&req=5

pone-0038745-g006: Effect of selective renal silencing of D2R in one kidney of mice without uni-nephrectomy on blood pressure and expression of inflammatory factors in the kidney and liver.Renal cortical D2R was silenced by the renal subcapsular infusion in the left kidney for seven days of Drd2 siRNA, via an osmotic minipump in adult male C57BL/6J mice (see Methods). A. Expression of D2R protein (55 kDa band) in renal cortex and liver was semi-quantified by immunoblotting. Results were corrected for GAPDH and expressed as % of NS siRNA treated kidneys. * P<0.05 vs non-silencing NS siRNA; n = 4/group. B. Systolic blood pressure measured under anesthesia in mice before and seven days after Drd2 siRNA infusion; n = 5/group. C. Renal cortical expression of TNFα, Ltα, NFkB1, MCP-1, MCP-2, IL-10, IL-11, osteopontin and collagen 1α1 mRNA was quantified by qRT-PCR, results corrected for expression of GAPDH mRNA, and expressed as fold change in comparison to their expression in mice treated with NS siRNA. *P<0.05 vs. NS; n = 5/group.
Mentions: In order to eliminate the confounding effect of uni-nephrectomy and the increase in blood pressure in the above experiments, we also studied the effect of chronic unilateral renal subcapsular infusion of Drd2 siRNA in mice with two intact kidneys. Selective down-regulation of Drd2 in one kidney (Figure 6A) had no effect on systolic blood pressure (Figure 6B), suggesting that the intact kidney, in the short-term, is able to compensate for the effects of decreased Drd2 expression in the treated kidney. The mRNA expression of TNFα, Ltα, NFκB1, MCP-1 and MCP-2 was increased in the treated kidney to the same extent as in treated uni-nephrectomized mice; NFkB1 and IL-10 were increased but to a lesser extent than in uni-nephrectomized mice. The mRNA expression of IL-11 was similarly decreased. In contrast the expression of the injury markers osteopontin and Col 1α1 was increased to a greater extent than in infused remnant kidney of uni-nephrectomized mice (Figure 6C).

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