Upregulation of Renal D ₅ Dopamine Receptor Ameliorates the Hypertension in D ₃ Dopamine Receptor–Deficient Mice

Abstract

D3 dopamine receptor (D3R) deficient mice have renin-dependent hypertension associated with sodium retention but the hypertension is mild. In order to determine if any compensatory mechanisms in the kidney are involved in the regulation of blood pressure with disruption of Drd3, we measured the renal protein expression of all dopamine receptor subtypes (D1R, D2R, D4R, and D5R) in D3R homozygous (D3−/−) and heterozygous (D3+/−) knockout mice and their wild-type (D3+/+) littermates. The renal immunohistochemistry and protein expression of D5R was increased (n=5/group) in D3−/−mice, renal D4R protein expression was decreased, while renal protein expressions of D1R and D2R were similar in both groups. Renal D5R protein expression was also increased in D3+/− (n=5/group) relative to D3+/+ mice, while D1R, D2R, and D4R protein expressions were similar in D3+/− and D3+/+ mice. The increase in renal D5R protein expression was abolished when D3−/− mice were fed a high salt diet. Treatment with the D1-like receptor antagonist, SCH23390, increased the blood pressure in anesthetized D3−/− but not D3+/+ mice (n=4/group), suggesting that the renal upregulation of D5R may have minimized the hypertension in D3−/− mice. The renal D5R protein upregulation was not due to increased transcription because renal mRNA expression of D5R was similar in D3−/− and D3+/+ mice. Our findings suggest that the renal upregulation of D5R may have minimized the hypertension that developed in D3−/− mice.

Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice

“…The rabbit polyclonal antibodies against dopamine receptors D 1 R (DRD1), D 3 R (DRD3) D 4 R (DRD4), and D 5 R (DRD5) were generated in our laboratory while rabbit polyclonal antibodies against D 2 R (EMD Millipore, Billerica, MA) and actin (Sigma-Aldrich, St. Louis, MO) were purchased. We have reported the specificity of our D 1 R antibody (17,19), D 3 R antibody (18), D 4 R antibody (21), D 5 R antibody (20), D 1 R antibody from Origene (Rockville, MD) (21), and D 2 R from EMD Millipore (12). The NOX4 (NADPH oxidase 4) affinity-purified antibody used in these studies was raised in rabbit against the peptide KVPSRRTRRLLDKSKT, which is 100% homologous to both rat (NCBI accession no.…”

Oxidative Stress in Hypertension: Role of the Kidney

“…D3( -/ -) mice also have increased renal AT1R expression but only a mild hypertension (344). This is attributed to a renal upregulation of D5 receptors, which prevents oxidative stress in D3 ( -/ -) mice (300). Thus, stimulation of D1-like and D2-like receptors activates antioxidant pathways while their impairment during hypertension exacerbates the oxidative stress induced by ANG II and its effects on Na + reabsorption.…”

Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity

“…Discovery of Novel D1 Dopamine Receptor PAMs hypertension in D3 knockout mice (Wang et al, 2013). Genetic deletion of D5 receptors in mice results in elevated blood pressure (Hollon et al, 2002;Yang et al, 2004), whereas the role of D1 receptors in regulating blood pressure is still unclear (Albrecht et al, 1996;Wang et al, 1999).…”