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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 the remaining kidney of uni-nephrectomized mice on blood pressure and expression on inflammatory factors in the kidney and liver.Renal cortical Drd2 was silenced by the renal subcapsular infusion for seven days of Drd2 siRNA, via an osmotic minipump in uni-nephrectomized 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 non-silencing siRNA treated kidneys. * P<0.05 vs non-silencing (NS) siRNA; n = 5/group. B. Systolic blood pressure measured under anesthesia in mice before and seven days after Drd2 siRNA infusion. * P<0.05 vs, NS siRNA; n = 5/group. C. Renal cortical expression of TNFα, Ltα, NFkB1, MCP-1, MCP-2, IL-10, IL-11 osteopontin, and Col 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-g005: Effect of selective renal silencing of D2R in the remaining kidney of uni-nephrectomized mice on blood pressure and expression on inflammatory factors in the kidney and liver.Renal cortical Drd2 was silenced by the renal subcapsular infusion for seven days of Drd2 siRNA, via an osmotic minipump in uni-nephrectomized 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 non-silencing siRNA treated kidneys. * P<0.05 vs non-silencing (NS) siRNA; n = 5/group. B. Systolic blood pressure measured under anesthesia in mice before and seven days after Drd2 siRNA infusion. * P<0.05 vs, NS siRNA; n = 5/group. C. Renal cortical expression of TNFα, Ltα, NFkB1, MCP-1, MCP-2, IL-10, IL-11 osteopontin, and Col 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: To determine further the role of D2R in the renal inflammatory reaction, we acutely and selectively silenced renal Drd2s in mice in order to avoid the confounding effects of systemic D2R deletion. Infusion of Drd2 siRNA for seven days in uni-nephrectomized mice decreased renal cortical expression of D2R by 50% but did not affect the expression of the receptor in the liver, indicating renal selectivity of the down-regulation (Figure 5A). As with systemic Drd2 deletion, treatment with Drd2 siRNA increased systolic blood pressure by about 20 mmHg (Figure 5B), an increase of the same magnitude of that observed in mice with systemic Drd2 deletion [3], [4]. This highlights the role of D2R in the regulation of blood pressure via the kidney. Subcapsular renal Drd2 silencing in uni-nephrectomized mice increased renal cortical mRNA expression of TNFα, Ltα, NFkB1, MCP-2 and IL-10, and simultaneously decreased the expression of IL-11. These results are similar to those found in mice with systemic Drd2 deletion, confirming the role of renal D2R in the regulation of the expression of inflammatory factors. Furthermore, the expression of osteopontin and Col 1α1, markers of tissue damage [34], was also increased in the kidneys with silenced D2Rs (Figure 5C).


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 the remaining kidney of uni-nephrectomized mice on blood pressure and expression on inflammatory factors in the kidney and liver.Renal cortical Drd2 was silenced by the renal subcapsular infusion for seven days of Drd2 siRNA, via an osmotic minipump in uni-nephrectomized 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 non-silencing siRNA treated kidneys. * P<0.05 vs non-silencing (NS) siRNA; n = 5/group. B. Systolic blood pressure measured under anesthesia in mice before and seven days after Drd2 siRNA infusion. * P<0.05 vs, NS siRNA; n = 5/group. C. Renal cortical expression of TNFα, Ltα, NFkB1, MCP-1, MCP-2, IL-10, IL-11 osteopontin, and Col 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-g005: Effect of selective renal silencing of D2R in the remaining kidney of uni-nephrectomized mice on blood pressure and expression on inflammatory factors in the kidney and liver.Renal cortical Drd2 was silenced by the renal subcapsular infusion for seven days of Drd2 siRNA, via an osmotic minipump in uni-nephrectomized 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 non-silencing siRNA treated kidneys. * P<0.05 vs non-silencing (NS) siRNA; n = 5/group. B. Systolic blood pressure measured under anesthesia in mice before and seven days after Drd2 siRNA infusion. * P<0.05 vs, NS siRNA; n = 5/group. C. Renal cortical expression of TNFα, Ltα, NFkB1, MCP-1, MCP-2, IL-10, IL-11 osteopontin, and Col 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: To determine further the role of D2R in the renal inflammatory reaction, we acutely and selectively silenced renal Drd2s in mice in order to avoid the confounding effects of systemic D2R deletion. Infusion of Drd2 siRNA for seven days in uni-nephrectomized mice decreased renal cortical expression of D2R by 50% but did not affect the expression of the receptor in the liver, indicating renal selectivity of the down-regulation (Figure 5A). As with systemic Drd2 deletion, treatment with Drd2 siRNA increased systolic blood pressure by about 20 mmHg (Figure 5B), an increase of the same magnitude of that observed in mice with systemic Drd2 deletion [3], [4]. This highlights the role of D2R in the regulation of blood pressure via the kidney. Subcapsular renal Drd2 silencing in uni-nephrectomized mice increased renal cortical mRNA expression of TNFα, Ltα, NFkB1, MCP-2 and IL-10, and simultaneously decreased the expression of IL-11. These results are similar to those found in mice with systemic Drd2 deletion, confirming the role of renal D2R in the regulation of the expression of inflammatory factors. Furthermore, the expression of osteopontin and Col 1α1, markers of tissue damage [34], was also increased in the kidneys with silenced D2Rs (Figure 5C).

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