Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro-inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1β. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances where high blood pressure is a critical risk factor. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of hypertension and discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies.

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.

The D ₂ dopamine receptor (D ₂ R) is important in the pathogenesis of essential hypertension. We have already reported that systemic deletion of the D ₂ R gene in mice results in reactive oxygen species (ROS)-dependent hypertension, suggesting that the D ₂ R has antioxidant effects. However, the mechanism of this effect is unknown. DJ-1 is a protein that has antioxidant properties. D ₂ R and DJ-1 are expressed in the mouse kidney and colocalize and coimunoprecipitate in mouse renal proximal tubule cells. We hypothesized that D ₂ Rs regulate renal ROS production in the kidney through regulation of DJ-1 expression or function. Heterozygous D ₂ ^+/− mice have increased blood pressure, urinary 8-isoprostanes, and renal Nox 4 expression, but decreased renal DJ-1 expression. Silencing D ₂ R expression in mouse renal proximal tubule cells increases ROS production and decreases the expression of DJ-1. Conversely, treatment of these cells with a D ₂ R agonist increases DJ-1 expression and decreases Nox 4 expression and NADPH oxidase activity, effects that are partially blocked by a D ₂ R antagonist. Silencing DJ-1 expression in mouse renal proximal tubule cells increases ROS production and Nox 4 expression. Selective renal DJ-1 silencing by the subcapsular infusion of DJ-1 siRNA in mice increases blood pressure, renal Nox4 expression, and NADPH oxidase activity. These results suggest that the inhibitory effects of D ₂ R on renal ROS production are at least, in part, mediated by a positive regulation of DJ-1 expression/function and that DJ-1 may have a role in the prevention of hypertension associated with increased ROS production.

The dopamine D ₂ receptor (D ₂ R) decreases renal reactive oxygen species (ROS) production and regulates blood pressure, in part, via positive regulation of paraoxonase 2. Sestrin2, a highly conserved antioxidant protein, regulates intracellular ROS level by regenerating hyperoxidized peroxiredoxins. We hypothesized that sestrin2 may be involved in preventing excessive renal ROS production and thus contribute to the maintenance of normal blood pressure. Moreover, the D ₂ R may decrease ROS production, in part, through the regulation of sestrin2. Renal sestrin2 expression was lower (−62±13%) in D ₂ R ^−/− than in D ₂ R ^+/+ mice. Silencing D ₂ R in human renal proximal tubule cells decreased sestrin2 expression (−53±3%) and increased hyperoxidized peroxiredoxins (2.9-fold). Stimulation of D ₂ R in renal proximal tubule cells increased sestrin2 expression (1.6-fold), decreased hyperoxidized peroxiredoxins (−61±3%), and reduced ROS production (−31±4%). Silencing sestrin2 in renal proximal tubule cells increased hyperoxidized peroxiredoxins (2.1-fold) and ROS production (1.3-fold). Silencing sestrin2 also abolished D ₂ R-induced decrease in peroxiredoxin hyperoxidation and partially prevented the inhibitory effect of D ₂ R stimulation on ROS production. Silencing paraoxonase 2 increased sestrin2 ubiquitinylation (2.8-fold), decreased sestrin2 expression (−30±3%), and increased ROS production (1.3-fold), peroxiredoxin hyperoxidation (2.9-fold), and lipid peroxidation (2.3-fold), and blocked the increase in sestrin2 that occurs with D ₂ R stimulation. In vivo renal selective silencing of sestrin2 by the renal subcapsular infusion of sestrin2 small interfering RNA (3 μg/day; 7 days) in mice increased renal oxidative stress (1.3-fold) and blood pressure. These results suggest that the D ₂ R, via paraoxonase 2 and sestrin2, keeps normal renal redox balance, which contributes to the maintenance of normal blood pressure.

Significance: Kidney diseases remain a worldwide public health problem resulting in millions of deaths each year; they are characterized by progressive destruction of renal function by sustained inflammation. Pyroptosis is a lytic type of programmed cell death involved in inflammation, as well as a key fibrotic mechanism that is critical in the development of kidney pathology. Pyroptosis is induced by the cleavage of Gasdermins by various caspases and is executed by the insertion of the N-terminal fragment of cleaved Gasdermins into the plasma membrane, creating oligomeric pores and allowing the release of diverse proinflammatory products into the extracellular space. Inflammasomes are multiprotein complexes leading to the activation of caspase-1, which will cleave Gasdermin D, releasing several proinflammatory cytokines; this results in the initiation and amplification of the inflammatory response. Recent Advances: The efficacy of Gasdermin D cleavage is reduced by a change in the redox balance. Recently, several studies have shown that the attenuation of reactive oxygen species (ROS) production induced by antioxidant pathways results in a reduction of renal pyroptosis. In this review, we discuss the role of pyroptosis in the pathogenesis of chronic kidney disease (CKD) and acute kidney disease; summarize the clinical outcomes and different molecular mechanisms leading to Gasdermin activation; and examine studies about the capacity of antioxidants, particularly Nrf2 activators, to ameliorate Gasdermin activity. Future Directions: We illustrate the potential influence of the deregulation of redox balance on inflammasome activity and pyroptosis as a novel therapeutic approach for the treatment of kidney diseases. Antioxid. Redox Signal . 35, 40–60.