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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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Renal inflammation and injury in D2−/− mice.Masson stained sections of D2+/+ mouse kidney (A and B) and D2−/− mouse kidney (C and D). H-E stained sections of D2+/+ mouse kidney (E) and D2−/− mouse kidney (F). G: glomerulus. PCT: proximal convoluted tubule. Proteinaceous casts are marked with arrows (F). Sections from 3 mouse kidneys per group were studied. G and H: Inflammatory cell infiltration. Kidney sections from D2+/+ (G) and D2−/− (H) mice were immunostained for the presence of macrophages and monocytes (arrows). The number of positive cells in 10 randomly selected fields was greater in D2−/− (68±3) than in D2+/+ (15±1, P<0.01) mice. Sections from 3 mouse kidneys per group were studied. I. Renal cortical expression of Col 1α1 mRNA determined by qRT-PCR. Results were corrected for expression of GAPDH mRNA and expressed as fold change in comparison to their expression in D2+/+ mice. *P<0.05 vs D2+/+; n = 5/group. J. Urinary microalbuminuria. Urine samples were collected for 24 h from mice in metabolic cages. Albumin was measured by ELISA. *P<0.04 vs. D2+/+; n = 5/group. Magnification: A and C: 100X; B, D, G and H: 400X; E-F: 200X.
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pone-0038745-g001: Renal inflammation and injury in D2−/− mice.Masson stained sections of D2+/+ mouse kidney (A and B) and D2−/− mouse kidney (C and D). H-E stained sections of D2+/+ mouse kidney (E) and D2−/− mouse kidney (F). G: glomerulus. PCT: proximal convoluted tubule. Proteinaceous casts are marked with arrows (F). Sections from 3 mouse kidneys per group were studied. G and H: Inflammatory cell infiltration. Kidney sections from D2+/+ (G) and D2−/− (H) mice were immunostained for the presence of macrophages and monocytes (arrows). The number of positive cells in 10 randomly selected fields was greater in D2−/− (68±3) than in D2+/+ (15±1, P<0.01) mice. Sections from 3 mouse kidneys per group were studied. I. Renal cortical expression of Col 1α1 mRNA determined by qRT-PCR. Results were corrected for expression of GAPDH mRNA and expressed as fold change in comparison to their expression in D2+/+ mice. *P<0.05 vs D2+/+; n = 5/group. J. Urinary microalbuminuria. Urine samples were collected for 24 h from mice in metabolic cages. Albumin was measured by ELISA. *P<0.04 vs. D2+/+; n = 5/group. Magnification: A and C: 100X; B, D, G and H: 400X; E-F: 200X.

Mentions: Masson staining of D2−/− mouse kidney sections showed glomerulosclerosis and dilation of renal tubules (Fig 1C–D). H-E staining showed the presence of tubular proteinaceous casts (Figure 1F). These lesions were not observed in D2+/+ mice (Figure 1A, B,E). The percentage of glomeruli showing more than 25% sclerosis was greater in D2−/− than D2+/+ mice (35±9% vs. 5±6%, P<0.01). There were more infiltrating macrophages/monocytes in kidney sections from D2−/− mice (Figure 1H) than D2+/+ mice (Figure 1G (68±3 vs.15±1 positive cells/10 fields, P<0.01). The level of mRNA expression of Col 1α1 was about 60% higher in renal cortex of D2−/− than D2+/+ mice (Figure 1I). Microalbuminuria, a functional parameter of renal damage, was 9-fold higher in D2−/− mice than in D2+/+ littermates (Figure 1J).


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)

Renal inflammation and injury in D2−/− mice.Masson stained sections of D2+/+ mouse kidney (A and B) and D2−/− mouse kidney (C and D). H-E stained sections of D2+/+ mouse kidney (E) and D2−/− mouse kidney (F). G: glomerulus. PCT: proximal convoluted tubule. Proteinaceous casts are marked with arrows (F). Sections from 3 mouse kidneys per group were studied. G and H: Inflammatory cell infiltration. Kidney sections from D2+/+ (G) and D2−/− (H) mice were immunostained for the presence of macrophages and monocytes (arrows). The number of positive cells in 10 randomly selected fields was greater in D2−/− (68±3) than in D2+/+ (15±1, P<0.01) mice. Sections from 3 mouse kidneys per group were studied. I. Renal cortical expression of Col 1α1 mRNA determined by qRT-PCR. Results were corrected for expression of GAPDH mRNA and expressed as fold change in comparison to their expression in D2+/+ mice. *P<0.05 vs D2+/+; n = 5/group. J. Urinary microalbuminuria. Urine samples were collected for 24 h from mice in metabolic cages. Albumin was measured by ELISA. *P<0.04 vs. D2+/+; n = 5/group. Magnification: A and C: 100X; B, D, G and H: 400X; E-F: 200X.
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pone-0038745-g001: Renal inflammation and injury in D2−/− mice.Masson stained sections of D2+/+ mouse kidney (A and B) and D2−/− mouse kidney (C and D). H-E stained sections of D2+/+ mouse kidney (E) and D2−/− mouse kidney (F). G: glomerulus. PCT: proximal convoluted tubule. Proteinaceous casts are marked with arrows (F). Sections from 3 mouse kidneys per group were studied. G and H: Inflammatory cell infiltration. Kidney sections from D2+/+ (G) and D2−/− (H) mice were immunostained for the presence of macrophages and monocytes (arrows). The number of positive cells in 10 randomly selected fields was greater in D2−/− (68±3) than in D2+/+ (15±1, P<0.01) mice. Sections from 3 mouse kidneys per group were studied. I. Renal cortical expression of Col 1α1 mRNA determined by qRT-PCR. Results were corrected for expression of GAPDH mRNA and expressed as fold change in comparison to their expression in D2+/+ mice. *P<0.05 vs D2+/+; n = 5/group. J. Urinary microalbuminuria. Urine samples were collected for 24 h from mice in metabolic cages. Albumin was measured by ELISA. *P<0.04 vs. D2+/+; n = 5/group. Magnification: A and C: 100X; B, D, G and H: 400X; E-F: 200X.
Mentions: Masson staining of D2−/− mouse kidney sections showed glomerulosclerosis and dilation of renal tubules (Fig 1C–D). H-E staining showed the presence of tubular proteinaceous casts (Figure 1F). These lesions were not observed in D2+/+ mice (Figure 1A, B,E). The percentage of glomeruli showing more than 25% sclerosis was greater in D2−/− than D2+/+ mice (35±9% vs. 5±6%, P<0.01). There were more infiltrating macrophages/monocytes in kidney sections from D2−/− mice (Figure 1H) than D2+/+ mice (Figure 1G (68±3 vs.15±1 positive cells/10 fields, P<0.01). The level of mRNA expression of Col 1α1 was about 60% higher in renal cortex of D2−/− than D2+/+ mice (Figure 1I). Microalbuminuria, a functional parameter of renal damage, was 9-fold higher in D2−/− mice than in D2+/+ littermates (Figure 1J).

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