Renal Dopamine Receptors, Oxidative Stress, and Hypertension

Abstract

Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.

Role of Nuclear Factor Erythroid 2–Related Factor 2 in the Oxidative Stress–Dependent Hypertension Associated With the Depletion of DJ-1

“…Antioxidants regulated by Nrf2, other than D 2 R and DJ-1, such as HO-1 could be involved in the antioxidant mechanism of DJ-1 and D 2 R. However, we have reported that the antioxidant effect of D 2 R is not related to HO-1 but rather due, in part, to HO-2 (5). Therefore, D 2 R stimulation increases the expression of some antioxidants such as HO-2 (7), PON2 (10), and DJ-1(11), independently of Nrf2 (Figure 6). …”

“…Deletion of any of the dopamine receptor genes in mice results in increased blood pressure by mechanisms that are dopamine receptor subtype-specific (4). In particular, D 2 −/− and D 5 −/− mice have hypertension that is associated with oxidative stress (5,6,7). …”

Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes

“…Dopamine is well known as a neurotransmitter. However, dopamine can regulate other cellular functions, including ion transport, smooth muscle contractility, hormone production, and cell proliferation (7)(8)(9). Dopamine can also regulate inflammation.…”

Sestrin2 Decreases Renal Oxidative Stress, Lowers Blood Pressure, and Mediates Dopamine D 2 Receptor–Induced Inhibition of Reactive Oxygen Species Production

“…This is the first report that demonstrates the role of sestirn2 in the regulation of blood pressure. The increase in renal ROS production, associated with activation of the adrenergic nervous system and intrarenal renin-angiotensin system (RAS), may affect renal sodium transport causing sodium and fluid retention and ultimately hypertension [9, 14, 33]. Interestingly, we found that sestrin2 silencing increased hyper-oxidized peroxiredoxins in human PRTCs.…”

“…ROS production is limited not only by decreased oxidant activity, but also by increased antioxidant defense [10, 14]. Peroxiredoxins are thiol-based antioxidant enzymes detoxifying ROS by oxidation of their two cysteine groups to cysteine sulfinic acid (Cys-SO 2 H) or cysteine sulfonic acid (Cys-SO 3 H), causing inactivation of peroxidase activity [16–19].…”