Hypertension (HTN) is a major contributor to kidney damage, leading to conditions such as nephrosclerosis and hypertensive nephropathy, significant causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). HTN is also a risk factor for stroke and coronary heart disease. Oxidative stress, inflammation, and activation of the renin–angiotensin–aldosterone system (RAAS) play critical roles in causing kidney injury in HTN. Genetic and environmental factors influence the susceptibility to hypertensive renal damage, with African American populations having a higher tendency due to genetic variants. Managing blood pressure (BP) effectively with treatments targeting RAAS activation, oxidative stress, and inflammation is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD. Interactions between genetic and environmental factors impacting kidney function abnormalities are central to HTN development. Animal studies indicate that genetic factors significantly influence BP regulation. Anti-natriuretic mechanisms can reset the pressure–natriuresis relationship, requiring a higher BP to excrete sodium matched to intake. Activation of intrarenal angiotensin II receptors contributes to sodium retention and high BP. In HTN, the gut microbiome can affect BP by influencing energy metabolism and inflammatory pathways. Animal models, such as the spontaneously hypertensive rat and the chronic angiotensin II infusion model, mirror human essential hypertension and highlight the significance of the kidney in HTN pathogenesis. Overproduction of reactive oxygen species (ROS) plays a crucial role in the development and progression of HTN, impacting renal function and BP regulation. Targeting specific NADPH oxidase (NOX) isoforms to inhibit ROS production and enhance antioxidant mechanisms may improve renal structure and function while lowering blood pressure. Therapies like SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing oxidative stress, inflammation, and RAAS activity, offering renal and antihypertensive protection in managing HTN and CKD. This review emphasizes the critical role of NOX in the development and progression of HTN, focusing on its impact on renal function and BP regulation. Effective BP management and targeting oxidative stress, inflammation, and RAAS activation, is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD.

The intracellular signaling events by which NADPH oxidase-generated reactive oxygen species (ROS) modulate vascular smooth muscle cell (VSMC) function and atherogenesis are yet to be entirely elucidated. We previously demonstrated that NADPH oxidase deficiency decreased atherosclerosis in apoE(-/-) mice and identified adhesion protein CD44 as an important ROS-sensitive gene expressed in VSMC and atherosclerotic lesions. Here, we examined the molecular mechanisms by which NADPH oxidase-generated ROS regulate the expression of CD44 and its principal ligand, hyaluronan (HA), and how CD44-HA interaction affects VSMC proliferation and migration and inflammatory gene expression in apoE(-/-) mice aortas. Thrombin-induced CD44 expression is mediated by transcription factor AP-1 in a NADPH oxidase-dependent manner. NADPH oxidase-mediated ROS generation enhanced thrombin-induced HA synthesis, and hyaluronan synthase 2 expression in VSMC. Hyaluronidase, which generates low molecular weight HA (LMW-HA), is induced in VSMC in a NADPH oxidase-dependent manner and LMW-HA stimulated ROS generation and cell proliferation in wild-type but not p47(phox-/-) VSMC, effects that were enhanced by thrombin pretreatment. Haptotactic VSMC migration toward HA was increased by thrombin in a CD44-dependent manner. HA expression in atherosclerotic lesions and plasma-soluble CD44 and HA levels were higher in apoE(-/-) compared with apoE(-/-)/p47(phox-/-) mice. HA-regulated pro-inflammatory gene expression was higher in apoE(-/-) than apoE(-/-)/p47(phox-/-) mouse aortas. GKT136901, a specific inhibitor of Nox1- and Nox4-containing NADPH oxidase activity, attenuated ROS generation and atherosclerosis and decreased CD44 and HA expression in atherosclerotic lesions. Together, these data suggest that increased CD44 and HA expression and CD44-HA-dependent gene regulation may play a role in atherosclerosis stimulated by NADPH oxidase activation.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and its prevalence increases with age. The irregular and rapid contraction of the atria can lead to ineffective blood pumping, local blood stasis, blood clots, ischemic stroke, and heart failure. NADPH oxidases (NOX) and mitochondria are the main sources of reactive oxygen species in the heart, and dysregulated activation of NOX and mitochondrial dysfunction are associated with AF pathogenesis. NOX- and mitochondria-derived oxidative stress contribute to the onset of paroxysmal AF by inducing electrophysiological changes in atrial myocytes and structural remodeling in the atria. Because high atrial activity causes cardiac myocytes to expend extremely high energy to maintain excitation-contraction coupling during persistent AF, mitochondria, the primary energy source, undergo metabolic stress, affecting their morphology, Ca²⁺ handling, and ATP generation. In this review, we discuss the role of oxidative stress in activating AF-triggered activities, regulating intracellular Ca²⁺ handling, and functional and anatomical reentry mechanisms, all of which are associated with AF initiation, perpetuation, and progression. Changes in the extracellular matrix, inflammation, ion channel expression and function, myofibril structure, and mitochondrial function occur during the early transitional stages of AF, opening a window of opportunity to target NOX and mitochondria-derived oxidative stress using isoform-specific NOX inhibitors and mitochondrial ROS scavengers, as well as drugs that improve mitochondrial dynamics and metabolism to treat persistent AF and its transition to permanent AF.

In acute sympathetic stress, catecholamine overload can lead to stress cardiomyopathy. We tested the hypothesis that cardiomyocyte NOX4 (NADPH oxidase 4)-dependent mitochondrial oxidative stress mediates inflammation and diastolic dysfunction in stress cardiomyopathy. Isoproterenol (ISO; 5 mg/kg) injection induced sympathetic stress in wild-type and cardiomyocyte (CM)-specific Nox4 knockout (Nox4^CM-/-) mice. Wild-type mice treated with ISO showed higher CM NOX4 expression, H₂O₂ levels, inflammasome activation, and IL18, IL6, CCL2, and TNFα levels than Nox4^CM-/- mice. Spectral flow cytometry and t-SNE analysis of cardiac cell suspensions showed significant increases in pro-inflammatory and pro-fibrotic embryonic-derived resident (CCR2^-MHCII^hiCX3CR1^hi) macrophages in wild-type mice 3 days after ISO treatment, whereas Nox4^CM-/- mice had a higher proportion of embryonic-derived resident tissue-repair (CCR2^-MHCII^loCX3CR1^lo) macrophages. A significant increase in cardiac fibroblast activation and interstitial collagen deposition and a restrictive pattern of diastolic dysfunction with increased filling pressure was observed in wild-type hearts compared with Nox4^CM-/- 7 days post-ISO. A selective NOX4 inhibitor, GKT137831, reduced myocardial mitochondrial ROS, macrophage infiltration, and fibrosis in ISO-injected wild-type mice, and preserved diastolic function. Our data suggest sympathetic overstimulation induces resident macrophage (CCR2^-MHCII⁺) activation and myocardial inflammation, resulting in fibrosis and impaired diastolic function mediated by CM NOX4-dependent ROS.

Aims: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are implicated in the pathophysiology of hypertension in chronic kidney disease patients. Genetic deletion of NOX activator 1 ( Noxa1 ) subunit of NOX1 decreases ROS under pathophysiological conditions. Here, we investigated the role of NOXA1-dependent NOX1 activity in the pathogenesis of angiotensin II (Ang II)-induced hypertension (AIH) and possible involvement of abnormal renal function. Results: NOXA1 is present in epithelial cells of Henle's thick ascending limb and distal nephron. Telemetry showed lower basal systolic blood pressure (BP) in Noxa1 ^−/− versus wild-type mice. Ang II infusion for 1 and 14 days increased NOXA1/NOX1 expression and ROS in kidney of male but not female wild-type mice. Mean BP increased 30 mmHg in wild-type males, with smaller increases in Noxa1 -deficient males and wild-type or Noxa1 ^−/− females. In response to an acute salt load, Na ⁺ excretion was similar in wild-type and Noxa1 ^−/− mice before and 14 days after Ang II infusion. However, Na ⁺ excretion was delayed after 1–2 days of Ang II in male wild-type versus Noxa1 ^−/− mice. Ang II increased epithelial Na ⁺ channel (ENaC) levels and activation in the collecting duct principal epithelial cells of wild-type but not Noxa1 ^−/− mice. Aldosterone induced ROS levels and Noxa1 and Scnn1a expression and ENaC activity in a mouse renal epithelial cell line, responses abolished by Noxa1 small-interfering RNA. Innovation and Conclusion: Ang II activation of renal NOXA1/NOX1-dependent ROS enhances tubular ENaC expression and Na ⁺ reabsorption, leading to increased BP. Attenuation of AIH in females is attributed to weaker NOXA1/NOX1-dependent ROS signaling and efficient natriuresis. Antioxid. Redox Signal . 36, 550–566.

Renal reactivity to angiotensin II (ANG II) is mediated by superoxide signaling produced by NADPH oxidase (NOX)A1/NOX1. Acute vasoconstriction of renal arteries by ANG was blunted in Noxa1^−/− compared with wild-type mice. NOXA1/NOX1/O₂^•− signaling was also observed in ANG II stimulation of vascular smooth muscle cells and isolated mesenteric resistance arteries, indicating that it contributes to ANG II-induced hypertension. A NOXA1/NOX1 assembly inhibitor (C25) has been characterized that inhibits superoxide production and ameliorates the effects of ANG II.