Nicotine-mediated redox and nitrosative stress in cardiorenal health

Abstract

Nicotine exposure is increasingly widespread due to the expansion of the use of non-combustible tobacco and nicotine replacement products, yet nicotine is still being framed as an addictive but relatively benign compound. This review synthesizes clinical and experimental evidence linking nicotine exposure to cardiorenal disease, emphasizing that risks persist after cessation. We discuss here a central novel concept that damage caused by nicotine in tissues is not determined solely by receptor signaling as nicotine exists in chemical forms capable of strong receptor-independent membrane diffusion. Mechanistically, we highlight convergent pathways of nicotine-induced cellular injury, focusing on redox stress, and underscoring major limitations in the field such as lack of studies in epithelial cells. We further emphasize the emerging paradigm that links nicotine and NOS biology in which reduced NO bioavailability, NOS uncoupling, and peroxynitrite-mediated protein nitration represent underappreciated drivers of persistent cardio-renal injury in response to nicotine. Finally, we outline gaps and research priorities needed to identify therapeutic strategies that specifically mitigate nicotine-driven oxidative and nitrosative injury in vulnerable populations with hypertension, diabetes, and CKD.

Nicotine exposure and sources of nicotine.

Despite the fact that nicotine is marketed as an addictive but “less harmful than smoking” compound, clinical and experimental evidence points to nicotine as a key driver of cardiovascular and renal damage. Smokers are more likely to develop hypertension and adverse cardiovascular events, including stroke and heart failure. In 2024, American Heart Association (AHA) issued an updated statement¹ on the use of smokeless tobacco products, raising additional concerns regarding oral nicotine products, such as gums, lozenges, and tablets. Cross-sectional analysis established that use of smokeless products, such as vapes, causes increase in blood pressure between 5 and 10 mm Hg and overall increase in cardiovascular risks^1,2 similar to harm from traditional cigarettes. Smokers exhibit higher rates of albuminuria and faster chronic kidney disease (CKD) progression³ (Figure 1). Effects of nicotine products consumed orally on cardiovascular and renal health are not established¹.

Figure 1. Sources of nicotine exposure and associated renal and cardiovascular pathologies.

Nicotine exposure occurs through multiple sources, including combustible tobacco products, non-combustible products, such as e-cigarettes/vapes, nicotine-containing replacement therapies, and through passive exposure. Nicotine exerts widespread systemic effects, contributing to cardiovascular and cerebrovascular disease (hypertension, heart attack, heart failure, and stroke), metabolic and immune disorders (type 2 diabetes and immune dysfunction), pulmonary disease, cancer, reproductive health pathologies, and CKD, including SRNG.

In January 2025, the FDA proposed the development of a tobacco product standard that would regulate nicotine yield by establishing a maximum nicotine level in cigarettes and certain other combusted tobacco products (FDA–2024–N–5471). Interestingly, nicotine, the main chemical in tobacco and many smoking cessation products, has been presented as an addictive but benign compound for decades⁴. This shifts basic and clinical research focus away from direct pathological effects of nicotine, validating the development of alternative ways of nicotine consumption (vaping, nicotine pouches, heating tobacco, chewing tobacco, etc.) while ignoring the harmful properties of nicotine itself. The main sources of nicotine exposure could be presented as follows:

• Combustible tobacco products: cigarettes, cigars, cigarillos, hookahs, and pipe tobacco.

• Non-combustible tobacco products: e-cigarettes, heat-not-burn products that use real tobacco but produce an inhalable aerosol instead of smoke, smokeless tobacco like nicotine pouches, chewing tobacco, snus, dip, etc.

• Nicotine-replacement products (NRP): nicotine gums, patches, lozenges, inhalers, and nasal sprays.

• Passive nicotine exposure.

According to 2022 National Health Interview Survey (NHIS) data, 19.8% (1 in 5) of U.S. adults reported current tobacco product use. According to this data, cigarettes remain the most commonly used type of tobacco product, and e-cigarettes are next with an increased use in adults since 2019. Vaping, presented as a healthier alternative to cigarettes, has become popular among the younger population. Across age groups in the US, adults aged 18–24 years have the highest prevalence of e-cigarette use, and adults aged 45–64 years had the highest prevalence of cigarette smoking⁵. Moreover, in 2024, 19.0% of U.S. middle and high school students (representing 5.28 million students) reported ever having used any tobacco product, and 8.1% (2.25 million students) reported current use of any tobacco product⁶, with the majority of them using e-cigarettes. Disposable vaping devices, which are very popular among students, often have high nicotine concentrations; moreover, the manufacturers of these devices are undefined with no regulation standards available. For example, one of the most popular brands of disposable vaping devices in the US, contains 5% nicotine⁷, and according to the 2024 National Youth Tobacco Survey, 36.1% of youth use these particular vapes. In 2018, 20.9% of US adults were reported to be former smokers, and NHIS reports that the ratio of former and current smokers in the US is 3:2. While comprehensive national statistics on nicotine exposure is not available, these data allow to suggest that almost half of the US population is currently or was in the past exposed to nicotine, while the long-term mechanistic effects of nicotine exposure are severely understudied.

While combustible and most non-combustible tobacco products are FDA-controlled, NRPs are FDA-approved, which further supports the public perception of them as a safe alternative to smoking. The perception of nicotine as a harmless substance has led to NRP being extensively used. Interestingly, the 5-year success rate of smoking cessation programs is reported to be only 20–30%⁸. A more recent study did not find consistent evidence that NRP use is related to the long-term success of smoking cessation; most importantly, the study showed that smokers remain interested in using NRP even 5 years after the completion of the smoking cessation program⁹. Table 1 highlights the substantial amounts of daily nicotine exposure across smoking products, including NRP nicotine-containing substances. Conservative estimations suggest that conventional cigarettes deliver the highest nicotine burden, with average smokers reaching approximately 1.7 to 2.4 mg/kg/day and heavy smokers exceeding 4 to 7 mg/kg/day, reflecting both high nicotine content per cigarette and frequent daily use¹⁰. Vaping results in lower but still significant exposure, particularly in heavy users, where nicotine intake can surpass 1.5 mg/kg/day depending on e-liquid concentration and puff frequency¹¹. Among NRPs, nicotine patches provide the lowest daily doses (generally less than 0.3 mg/kg/day), while gum and lozenges yield higher exposure (up to 40–80 mg/kg/day) but remain below that of cigarettes and heavy vaping. Overall, while combustible tobacco products produce the highest systemic nicotine exposure, and vaping occupies an intermediate range with high variability, CDC-recommended NRP regimens still deliver relatively high and persistent nicotine doses. Thus, one could surmise that NRPs are generally associated with lower consumption if taken according to the manufacturer’s instructions – unfortunately, on the contrary, the use of NRP often leads to continuous nicotine consumption without a clinical “smoking risk” status typically applied to smoking and vaping patients¹². Moreover, in nephrology, exposure to NRP in kidney donors and transplant patients generally does not qualify as “smoking” in clinical charts, is not being taken into consideration when transplant quality and patient suitability are being evaluated and thus poses a hidden risk. While we can usually estimate patient’s nicotine exposure when they use combustible and non-combustible tobacco products, it is very hard to assess NRP and passive nicotine exposure¹³, since these sources of nicotine are not perceived as dangerous as smoking and often are not reported to the health provider.

Table 1. Smoking product consumption and variable sources of nicotine.

Average nicotine exposure ranges calculated for a 70-kg person. Daily nicotine consumption derived from average (12 mg per cigarette or 30 mg/ml of e-liquid) and heavy (12–20 mg per cigarette or 30–60 mg/ml of e-liquid) consumers. Nicotine replacement therapy values are assembled from CDC approved treatment recommendations, and do not include calculations for individuals that augment or deviate from prescribed treatment strategies.

Exposure type	Conventional smoking and vaping		Over-the-counter Nicotine Replacement Therapy
	Cigarette	Vaping	Nicotine Patch	Nicotine Gum	Nicotine Lozenge
Nicotine content in tobacco products	8–20 mg (avg: 12)	3–60 mg/ml (avg: 30)	7, 14, or 21 mg	2.0 or 4.0mg	2.0 or 4.0mg
Average amount consumed per day (average consumer)	10–14 cigarettes (CDC, 01/2018)	100–200 puffs (~1–2mL)	1 × 24-hour 7 or 14 mg patch	8–12 pieces of 2.0 mg or 4–6 pieces of 4.0 mg	1 × 2.0 mg every 1–2 hours or 5 every 6 hours, 9–20 per day
Average amount consumed per day (heavy consumer)	>25 cigarettes10	365 puffs11	1 × 24-hour 14mg or 21mg patch	13–20 pieces of 2.0 mg or 7–10 pieces of 4.0 mg	1 × 4.0 mg every 1–2 hours or 5 every 6 hours, 9–20 per day
Nicotine exposure range (average consumer) mg/kg/day	1.7–2.4	0.4–0.9	0.1–0.2	0.2–0.3	0.3–0.6
Nicotine exposure range (heavy consumer) mg/kg/day	4.2–7.14	>1.5	0.2–0.3	0.4–0.6	0.5–1.1

Why smoking cessation alone falls short: a nephrologist’s view

Despite decades of cessation encouragement efforts, in 2021 in the USA 22.0% of people aged 12 or older reported nicotine consumption via tobacco products or vaping (2021 National Survey on Drug Use and Health). While quitting is a critical step, damage elicited by nicotine persists decades after cessation^14,15. Rodent studies linked nicotine to chronic kidney disease (CKD)^16–18, and prospective and population-based studies confirmed that nicotine perpetuates kidney pathology and augments the risk of proteinuria^19–21. Prospective studies also showed that secondhand smoke exposure increases the risk of CKD^22,23. In subjects with hypertension and patients with pre-existing renal disease, smoking-related kidney pathology is even more striking^24–29. Although smoking cessation remains the cornerstone of risk reduction, growing evidence indicates that cessation of nicotine exposure alone is often insufficient to reverse established end-organ damage, particularly in the cardiovascular and renal systems. This fact is possibly connected to the limited ability of renal cells to regenerate and recover after chronic injury (see more detailed discussion below in SRNG section). Epidemiologic and experimental studies demonstrate that prior smoking is associated with persistent cardiovascular risk, endothelial dysfunction, and accelerated CKD progression long after cessation, consistent with durable structural, metabolic, and epigenetic remodeling rather than purely acute toxic effects^30–33. Importantly, there are no approved therapies that specifically target nicotine-induced cardio-renal injury, and individuals attempting to quit continue to be exposed to pharmacologic nicotine through NRP, which, while reducing combustion-related toxins, may perpetuate nicotine-driven cellular stress pathways. This issue is particularly relevant for patients with hypertension, diabetes, and established cardiovascular or kidney disease, who exhibit heightened susceptibility to nicotine-induced oxidative, inflammatory, and metabolic injury and experience worse outcomes compared with non-smokers^34,35. This emphasizes a critical gap in our understanding of nicotine-mediated damage and highlights the need to define new disease-modifying pathways tailored to nicotine-exposed populations, where nicotine-associated pathology may be biologically distinct from that observed in otherwise healthy smokers.

Nicotine: beyond receptor binding.

Textbook biological actions of nicotine are exerted by binding to nicotinic acetylcholine receptors (nAChRs), which are pentameric ligand-gated cation channels³⁶. Nicotine binds to an extracellular orthosteric site; receptor activation opens a pore that conducts Na⁺/K⁺ and often Ca²⁺, driving depolarization and Ca²⁺-dependent signaling. Importantly, nAChRs are signaling receptors, they do not function as nicotine “transporters”; nicotine or acetylcholine are ligands that binds and gates the channel, and transported Ca²⁺ then further acts as a potent intracellular signal transducer. Both vascular and renal human cells expressed nAChRs but their composition and function are still under investigation. There are sixteen nAChR subunits identified, including ten α, four β, as well as γ, δ, and ε nAChR subunits, that form pentameric nAChRs in various combinations³⁷. The Staruschenko Lab Hypertension Atlas³⁸, which reports RNA-seq data from rat kidney, heart, and liver, detected expression of nAChR in renal and heart tissues. Both renal cortex and medulla exhibited the highest abundance of Chrna2, Chrna7, Chrnb1, Chrnb2, Chrne genes, encoding for nAChRα2, nAChRα7, nAChRβ1, nAChRβ2, nAChRε subunits; and heart tissue analysis presented with highest abundance of Chrna7, Chrna4, Chrnb1, Chrnd, and Chrng, encoding nAChRα7, nAChRα4, nAChRβ1, nAChRδ, and nAChRγ subunits. The different subunit distribution could result in ionotropic or metabotropic response to nicotine or acetylcholine and variation in the action of nAChR in different tissues. However, this conventional knowledge needs to be reviewed in the context of more intricate and often overlooked information regarding receptor-independent routes of nicotine entry into the cells³⁹. Depending on pH, nicotine can exist in three interconvertible forms: freebase (unprotonated), monoprotonated, and diprotonated nicotine⁴⁰ (Figure 2). Diprotonated nicotine is prevalent under highly acidic conditions. This form is low in most tobacco or vaping products because such a low pH is rarely reachable. In practice, only freebase and monoprotonated nicotine contribute to nicotine absorption in the human body. Of note, freebase nicotine is uncharged and lipophilic, readily crossing the cell membrane in seconds⁴¹. In contrast, protonated forms are charged and more water-soluble, crossing membranes more slowly and less efficiently (Figure 2). In tobacco leaves, nicotine is mostly present in protonated form, which is not as readily bioavailable. However, combustible tobacco products have long been engineered to create alkaline pH forms (with extreme alkalinity up to pH 11 in vaping products) and optimize nicotine to improve cell absorption. In cigarettes, the fraction of freebase nicotine in cigarette smoke varies by brand, ranging from a few percent up to 50%⁴². Smokeless tobacco and NRPs (e.g., chewing tobacco and nicotine gums) are buffered to an alkaline pH to increase the freebase concentration and facilitate nicotine absorption through mucous membranes and the skin⁴³. Vapes are highest pH tobacco products (and thus, higher freebase nicotine concentration) has been associated with greater nicotine absorption and greater cardiovascular effects⁴⁴. Vaping products allow the delivery of mainly freebase nicotine (up to 95%), with nicotine salts (monoprotonated form) being incorporated as a “smoother” alternative, as freebase nicotine decreases inhalability⁴⁵. Thus, the proportion of nicotine in freebase form compared to protonated form, as well as patient acid–base status, can influence how quickly and how much nicotine is absorbed during smoking or vaping. Alternatively, at physiological pH, when a substantial fraction of nicotine is protonated, an organic cation transporter (OCT) system may become key for nicotine transport in specific tissues (notably kidney and liver). Particularly, the SLC22 organic cation transporter family (e.g., OCT2/SLC22A2 in the kidney) is proposed as a determinant of renal uptake of nicotine: human genetic variation in OCT2 measurably impacts nicotine/cotinine pharmacokinetics in controlled infusion studies, supporting the contribution of this transporter to nicotine handling^46,47. According to SusztakLab Kidney Biobank data⁴⁸, all renal cells, including podocytes, express these transporters, with the highest abundance found in tubular cells.

Figure 2. Source-dependent nicotine form determines membrane permeability.

Nicotine exists in diprotonated, monoprotonated, and non-ionized (free-base) forms, with the relative abundance of each species determined by pH. Combustible tobacco products predominantly deliver monoprotonated nicotine, which exhibits slower passive diffusion across lipid bilayers. In contrast, nicotine salts and free-base nicotine used in e-cigarette formulations predominantly contain a non-ionized form of nicotine, resulting in a markedly higher fraction (>90%) of membrane-permeable nicotine⁴¹. Importantly, nicotine replacement therapy products, such as nicotine gums and lozenges, contain a significant fraction (25%) of unprotonated nicotine.

Collectively, these observations demonstrate that cellular nicotine exposure is not dictated solely by nAChR engagement, but by a complex interplay between nicotine chemistry, product formulation, acid-base balance, tissue pH, and transporter abundance. Considering the observations outlined above, individuals with metabolic or respiratory alkalosis and salt-sensitive (low-renin) hypertension who consume vaping products constitute a highly vulnerable, high-risk population. Receptor-independent membrane diffusion and OCT-mediated uptake can substantially shape intracellular nicotine burden, particularly in highly perfused and excretory organs such as the kidney. Appreciating these noncanonical entry routes is essential for understanding nicotine’s systemic and tissue-specific effects, including redox toxicity that cannot be explained by receptor signaling alone.

Nicotine’s effects on cardiovascular and renal health.

Autopsy case reports suggest that major targets for nicotine exposure and accumulation in the human body are blood vessels, the brain, and the kidney⁴⁹. This correlates with clinical findings that for smoking patients, the time of the first stroke onset is 10 years earlier than for nonsmoking patients⁵⁰. Moreover, the kidneys are responsible for nicotine clearance⁵¹. Less than 5% of circulating nicotine in protein-bound⁵², thus nicotine is easily transferred through glomerular filtration barrier (GFB) leading to wide exposure of the renal cells to nicotine. Approximately 10% of absorbed nicotine is excreted in urine as is, with the remainder appearing as metabolites (primarily cotinine and hydroxylated products)^53,54. In rodent models, nicotine exposure leads to measurable cotinine in kidney tissue at levels similar to plasma concentrations seen in smokers (e.g., ~60–130 ng/mL plasma cotinine); kidneys show biologic responses (oxidative stress and pro-fibrotic signaling) consistent with local tissue exposure, which implies that nicotine itself or its metabolites accumulate sufficiently in renal tissue to activate local pathways⁵⁵. Additionally, a cross-sectional data analysis revealed negative correlation between nicotine metabolism rate, and kidney function⁵⁶, suggesting that exposure to nicotine is detrimental to kidney cells. Of note, the mechanisms of this damage are not well understood.

Nicotine consumption has adverse effects on overall cardiovascular health. In 2021, the study by Khan et al., using data from 106,165 adults in nine population-based cohorts in the US, reported long-term risks for cardiovascular events as 46.0% and 34.7% in middle-aged men and women, respectively, with higher competing hazard ratios for the first presentation being a fatal event in smokers than in non-smokers⁵⁷. It is well-established that nicotine impacts the cardiovascular system by promoting sympathetic overactivation, oxidative stress, and endothelial dysfunction. Smoking was strongly associated with worse cardiovascular and kidney disease outcomes in several observational studies^28,58. Its effects collectively contribute to multiple cardiac and renal pathologies, including vascular (i.e. atherosclerosis and stroke), myocardial issues, hypertension and heart failure, arrhythmias, chronic kidney disease, and increased susceptibility to cardiovascular diseases overall⁵⁹. Data from The Study of Heart and Renal Protection (SHARP) show that smoking significantly increased the risks for vascular and nonvascular morbidity and mortality, although it was not associated with end-stage kidney disease (ESRD) development³, however, it should be noted that current smokers enrolled in SHARP had relatively low cigarette consumption (average, 10 cigarettes per day), and smoking status was only assessed at the starting point. Multiple risk factor intervention trial (MRFIT) which included heavy smokers (>30 cigarettes per day) reported an association between smoking and ESRD⁶⁰. Moreover, population studies also showed an increased risk of ESRD development in current smokers compared to patients who never smoked⁶¹.

It is established that nicotine induces an elevation of blood pressure and heart rate, as well as dysregulation of cardiac function, by activation of the sympathetic nervous system with the release of catecholamines such as norepinephrine⁶². Norepinephrine binds to α1 and α2 adrenergic receptors in vascular smooth muscle, facilitating Ca²⁺ ion influx and stored Ca²⁺ release, inhibiting adenylyl cyclase activity, thus regulating arteriolar resistance, venous capacitance, and smooth muscle vasoconstriction^63,64. Nicotine in electronic cigarettes induced an increase in sympathetic nerve activity, which was accompanied by increases in blood pressure and heart rate, while decreasing baroreflex response and arterial compliance⁶⁵. Nicotine consumption enhanced myocardial contractility through nAChR-induced sympathetic activation⁵⁹, primarily via the α7-nAChR receptor, which also plays a role in blood pressure regulation through baroreceptor modulation as shown in rodent models^66,67. Moreover, in mice models, nicotine derived from both traditional cigarettes and electronic cigarettes-induced cardiac hypertrophy in a time-dependent manner⁶⁸. Smoking was shown to alter both systemic and pulmonary blood pressure. Importantly, nicotine is known to damage the endothelium, reducing vasodilation and impairing blood flow: smoking contributes to endothelial dysfunction through increased oxidative stress and inflammation which was shown in comparative and crossover studies, as well as in human endothelial cells^69–71. Endothelial dysfunction contributes to impaired relaxation in both resistance and conductance vessels, which is linked to hypertension development⁷². Prolonged administration of nicotine in animal models has been shown to precipitate damage resulting in increased blood pressure, heart rate, cardiomyocyte inflammation, atherosclerosis, cardiac fibrosis, cardiac hypertrophy, and vascular endothelial dysfunction^73,74.

Nicotine has been identified as a major risk factor for kidney disease in the general population, and its effects were reported to be especially prominent in patients with diabetes and hypertension^75,76. The Kidney Disease Improving Global Outcomes (KDIGO) recommends that patients with diabetes and CKD avoid tobacco products and reduce secondhand smoke exposure⁷⁷. KDIGO recommends smoking cessation to patients with CKD and diabetes and also highlights the sparsity of available studies evaluating the effects of tobacco products, including regular cigarettes, electronic cigarettes, and nicotine replacement products⁷⁷. The link between smoking, progression of CKD, and a decline in renal function is well-established. The KDIGO guidelines recommend offering smoking cessation programs, which include options like NRPs (which only reduce nicotine consumption), to all eligible patients with CKD and those awaiting or having received a kidney transplant⁷⁷. Nicotine consumption and metabolism are linked to changes in eGFR, with the majority of studies showing that smoking is associated with an increase in eGFR due to compensatory hyperfiltration^58,78. A few studies have shown the opposite effect, which could possibly be explained by an initial decrease in renal plasma flow caused by smoking before glomeruli are damaged or different levels of nicotine exposure⁵⁸. Moreover, smoking is an independent factor for proteinuria in healthy subjects^79,80. Of note, smoking is a major risk factor for renal vascular pathology, increasing the risk of renal artery stenosis⁸¹. Data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL, NCT00081731) clinical trial suggest that smokers develop vascular pathology and composite endpoint events (defined as the first occurrence of stroke, cardiovascular or renal death, myocardial infarction, congestive heart failure, renal replacement) at a younger age compared to non-smokers⁸¹.

Multiple reports highlight nicotine’s contribution to glomerular and tubular renal pathologies²⁴. Documented glomerular lesions associated with nicotine consumption include Smoking-Related Nodular Glomerulopathy (SRNG, discussed in more details below)²⁴ and nicotine-induced endothelial injury⁸². Nicotine was also shown to increase proteinuria, promoting albumin-induced tubular damage and oxidative stress, as well as pathological activation of α7-nAChR in renal tubular cells⁸³. The 2023 analysis of the NEPTUNE study showed that, in patients with proteinuric glomerulopathies, the prevalence of active smoking, former smoking, and exclusive passive smoking among adults at baseline was 14.6%, 29.1%, and 4.9%, respectively⁵⁸. Passive smoke exposure was 16.7% among children with glomerulopathies⁵⁸. These numbers highlight the overwhelming contribution of nicotine to glomerular pathology development.

Smoking-Related Nodular Glomerulopathy (SRNG).

Chronic smoking in hypertensive subjects may lead to SRNG, a pathology presenting with an expanded mesangial matrix, podocyte loss, glomerular and tubular basement membrane thickening, and vascular hyalinosis^24,84 (Figure 3). Although the association between smoking and idiopathic nodular glomerulosclerosis has been recognized for decades, only recently smoking was identified as a driver of this distinct renal disease phenotype⁸⁵. Traditionally, nodular glomerulosclerosis was labeled “idiopathic” because a clear cause was not recognized; however, recent data have highlighted smoking as its cause, shifting the perception of this disease to a smoking-associated entity. The mechanisms of SRNG are unknown; pathologically, it mimics diabetic nephropathy without clinical evidence of diabetes or alterations in glucose metabolism^{24–29,86 87}. Clinical reports have presented an SRNG as a pathological condition characterized by the onset of diabetic-like glomerulopathy in subjects with no history of diabetes.^24–29,86 However, diffuse mesangial sclerosis can also occur in SRNG without nodules²⁴, which is typical in diabetic nephropathy (DN). SRNG can also present with chronic thrombotic microangiopathy, manifested through double contouring by light microscopy and subendothelial space widening by electron microscopy, as well as vascular sclerosis, medial hypertrophy, and hilar neo-vascularization²⁴. SRNG was observed in seniors with a history of chronic smoking and hypertension²⁵ and in young people exposed to nicotine due to passive smoking⁸⁶. It is strongly associated with smoking, hypertension, and obesity²⁶. Patients with SRNG present with proteinuria and renal insufficiency, without evidence of diabetes or hyperglycemia, which serves as a key distinguishing factor for DN and SRNG. Despite the similarity in glomerular pathology with DN, SRNG is strongly associated with hypertension⁸⁸.

Figure 3. Idiopathic Nodular Glomerulosclerosis (Smoking-Related Nodular Glomerulopathy) in a female smoker.

All pictures were taken at 200x magnification. A. Hematoxylin & eosin staining. B. Periodic acid Schiff staining. C. Jones Silver staining. All images show prominent nodular expansion of the mesangium with mild to moderate mesangial hypercellularity. The nodular material is bright PAS-positive and argyrophilic. It is Congo red negative, and no light chain restriction was noted by immunofluorescence.

Collectively, epidemiologic, clinical, and experimental studies establish strong associations between nicotine exposure and adverse cardiovascular and renal outcomes. However, despite the consistency of these observations across populations and model systems, the cellular and molecular mechanisms by which nicotine directly injures vascular, cardiac, and renal tissues remain poorly defined. This lack of mechanistic insight represents a critical knowledge gap that limits causal interpretation and constrains the development of targeted interventions to mitigate nicotine-associated cardio-renal disease.

Mechanisms of nicotine-induced cardiovascular and renal damage: redox stress.

Nicotine is increasingly recognized as a major determinant of oxidative stress and disruptor of cellular metabolism; however, the literature on specific reactive oxygen species (ROS) types triggered by nicotine exposure remains limited, with most studies examining ROS species “in general”, rather than specific individual ROS subtypes, such as radical (superoxide anion, hydroxyl, peroxyl, nitric oxide radicals and others) vs non-radical (hydrogen peroxide, etc) ROS. It was hypothesized that smoking induces nodular glomerulosclerosis through the formation of advanced glycosylation end products with the induction of oxidative stress⁸⁵. Across multiple tissues, nicotine exposure is associated with increased ROS generation, depletion of antioxidant defenses, and activation of redox-sensitive stress signaling such as MAPKs, NF-κB) that drives inflammation, cell death, and maladaptive remodeling^73,89–92. Mechanistically, nicotine-linked redox stress is most consistently attributed to two major ROS sources, mitochondria (mtROS) and NADPH oxidases (NOX)^73,89,93,94. In cultured human podocytes, terminally differentiated and non-regenerating cells, nicotine increased intracellular ROS (measured by DCFH) and triggered apoptosis through downstream stress-kinase pathways, providing a plausible direct mechanism for smoking/nicotine-associated progression of proteinuric kidney disease^16,91. In was further shown in DN models that nicotine can amplify podocyte superoxide production, and upregulate lipid-handling pathways such as CD36, linking oxidative stress to metabolic and lipotoxic vulnerability of the glomerular filtration barrier¹⁶. Furthermore, nicotine has been shown to promote NRLP3 inflammasome-associated podocyte injury, further connecting oxidative stress to inflammatory cell death and glomerular barrier dysfunction⁹⁵. Chronic nicotine exposure increased renal redox stress markers in renal cortex and worsened ischemia-reperfusion injury phenotype in vivo, consistent with a potential “redox priming” effect that lowers injury thresholds¹⁷. Interestingly, chronic nicotine administration also augmented renal oxidative stress and damage through transcriptional activation of p66Shc (a redox-regulatory adaptor that can amplify mitochondrial ROS and apoptotic susceptibility); p66Shc was reported to potentiate nicotine-driven lipotoxic oxidative stress in renal proximal tubule cells^90,96. Effects of nicotine have been relatively well studied in vascular cells; it can directly alter the phenotype of human primary vascular smooth muscle cells (VSMC) via nAchR -linked signaling, promoting their transition from contractile to synthetic function, which is a remodeling program that is commonly known to be redox-sensitive⁹⁷. Nicotine was shown to stimulate pro-calcific remodeling in human subjects, which was shown by in vitro studies to be mediated by activation of α7 and α3 nAChRs in VSMCs, increase in intracellular Ca²⁺, and NOX5-dependent oxidative stress⁹⁴. In mice in vivo, nicotine also promoted atherosclerosis and induced endothelial pyroptosis via ROS–NLRP3 inflammasome activation in human aortic endothelial cells, further linking oxidant stress to cell death and plaque progression⁹⁵. In diet-induced rat model of obesity, oral nicotine administration aggravated endothelial dysfunction with increased oxidative stress and vascular inflammation, suggesting that nicotine can synergize with metabolic risk states to intensify endothelial redox injury⁹⁸.

In the heart, in vivo nicotine exposure increased myocardial mitochondrial ROS, shifted redox balance towards lower glutathione abundance, and promoted hypertrophy, fibrosis, and functional impairment; these phenotypes were attenuated by targeting mtROS with mitochondria-directed antioxidant mitoTEMPO, supporting mtROS as an upstream mechanistic node rather than a biomarker⁷³. Nicotine was also reported to promote cardiomyocyte apoptosis through oxidative stress and altered expression of apoptosis-related genes, supporting its involvement in cytotoxic cellular programing in cultured cardiomyocytes⁹⁹. Nicotine can disrupt mitochondrial quality control by increasing Drp1-mediated fission and impairing mitophagic flux in the cardiomyocytes through ROS-dependent activation of stress kinases p38/JNK and reduced lysosomal protease activity⁹³. It has been consistently reported in cardiac tissues that ROS and mitochondrial dysfunction feed forward into maladaptive metabolic reprogramming that includes impaired oxidative phosphorylation, altered mitochondrial dynamics, and reduced bioenergetic capacity^73,89,93. Notably, mechanistic directionality is context-dependent; in isolated mitochondrial preparations, nicotine was shown to interact with electron transport chain (ETC) components and directly modulate superoxide generation¹⁰⁰. Thus, existing studies support the concept that nicotine acts as a potent driver of redox imbalance across renal, vascular, and cardiac tissues, with mitochondria and NADPH oxidases emerging as dominant sources of pathologic ROS. However, despite extensive associations with “oxidative stress,” the precise molecular species, subcellular sources, and temporal dynamics of nicotine-induced ROS remain poorly defined, limiting mechanistic resolution.

Nicotine, NOS signaling, and the shift from NO bioactivity to nitrosative stress.

A consistent theme across vascular, cardiac, and, to a lesser extent, renal studies is that nicotine exposure is associated with reduced nitric oxide (NO) bioavailability and/or a pathological shift in NOS output toward production of reactive nitrogen species (RNS), particularly peroxynitrite (ONOO⁻) (a process commonly termed nitrosative stress)^92,101. Mice studies shown that nicotine can impair NO signaling both by limiting NO production (e.g., diminished eNOS function) and by accelerating NO consumption through reactions with superoxide (O₂⁻) to generate ONOO⁻, leaving tissue “footprints” such as 3-nitrotyrosine^101–103. A direct mechanism linking nicotine to endothelial oxidant stress is tetrahydrobiopterin (BH4) depletion-driven eNOS (NOS3) uncoupling, where eNOS shifts from generating NO to generating superoxide; nicotine reduces GTP cyclohydrolase-1 (GTPCH1, rate-limiting enzyme for BH4 synthesis), increases ROS, and induces endothelial dysfunction, which is reversible by BH4/sepiapterin or GTPCH1 restoration⁹². This mechanism is biologically consistent with broader NOS biochemistry showing that inadequate BH4 shifts eNOS from producing NO toward producing superoxide, thereby amplifying oxidative/nitrosative stress^104,105. In addition, nicotine has been linked to induction of inducible NOS (iNOS, NOS2) in the vasculature, which can increase NO flux under inflammatory/stress conditions; in the presence of elevated superoxide (e.g. during redox stress resulting from dysfunctional mitochondria) would favor peroxynitrite formation and nitrative modification of proteins^106,107. In a murine arterial stiffness model, a SIRT1 gain-of-function protected against nicotine-induced arterial stiffening, and nicotine was shown to increase vascular iNOS and 3-nitrotyrosine and was mechanistically connected to peroxynitrite-mediated SIRT1 inactivation, thereby placing RNS as a functional driver of disease-related vascular remodeling¹⁰¹. Nicotine can alter NO biology beyond the vasculature, including modulation of NO metabolite levels and NOS-related signaling in the brain, indicating that nicotine-NOS interactions are not limited to one tissue and may be sex- and region-dependent^108,109. These broader observations reinforce that nicotine can intersect with NOS pathways at multiple regulatory levels (expression, coupling state, and substrate/cofactor availability), and that the overall phenotype likely depends heavily on the local redox environment. In renal injury contexts, nicotine exposure has been associated with increased nitrotyrosine in kidney tissue, consistent with nitrative stress and peroxynitrite biology during ischemic or inflammatory injury. For example, chronic nicotine exposure exacerbated renal ischemia/reperfusion injury and increased kidney nitrotyrosine levels alongside other oxidative stress markers¹⁷. While these data do not fully resolve which NOS isoform predominates in each renal compartment, they support a model in which nicotine increases the probability of a NO-to-ONOO⁻ shift in vivo, particularly under concurrent ROS-generating conditions that are common in CKD and acute injury. Moreover, nicotine is a source for Tobacco-Specific Nitrosamines (TSNAs), such as NNK and NNN¹¹⁰. While both NNK and NNN are formed during tobacco product manufacturing¹¹⁰, the transformation of nicotine into TSNAs also occurs endogenously^111,112. TSNAs has been linked to various cancers, moreover, their non-carcinogenic effects include effects on cellular metabolism, oxidative stress, and inflammation¹¹³.

Key unresolved questions and gaps in knowledge.

In summary, existing studies strongly associate nicotine exposure with oxidative and nitrosative stress across renal, vascular, and cardiac tissues; however, the field remains focused on receptor-linked signaling, while direct, non-receptor-mediated actions of nicotine are rarely interrogated. This gap is particularly important for understanding chronic and long-lasting tissue damage, where sustained intracellular accumulation, mitochondrial interactions, and transporter-mediated handling of nicotine may be more relevant than acute nAChR activation. Important limitation when accessing the evidence of nicotine effects on oxidative and nitrosative stress is that the term “ROS” is used broadly and imprecisely in the literature, with limited resolution of species, subcellular sources, timing, and downstream targets, hindering causal inference. Finally, understanding nicotine’s actions and evaluating the safety profile of NRPs is limited by the relative scarcity of studies examining nicotine alone. The majority of available evidence was derived from research on traditional combustible cigarettes or electronic cigarettes, where nicotine is delivered alongside numerous other bioactive compounds, making it difficult to attribute the observed effects specifically to nicotine. Importantly, limited number of studies on cardiovascular effects of NRP are available. More focused, well-controlled studies using nicotine alone at physiologically and therapeutically relevant doses are needed to clearly define its independent mechanistic role in cardiovascular and renovascular pathology. Moreover, while the studies provide evidence on nAChR-dependent action of nicotine, nicotine’s receptor-independent action remains unexplored.

Another understudied factor in investigating nicotine-associated mechanisms is genetic variability in nicotine metabolism and influence of genetics on nicotine-mediated injury susceptibility. Variations in CYP2A6 (Cytochrome P450 2A6), primary enzyme responsible for nicotine metabolism contribute to differences in smoke cessation success. Common and rare CYP2A6 alleles (null, reduced- and increased-function, and copy-number variants) produce large variability in nicotine clearance, the nicotine metabolite ratio^114,115. Moreover, twin studies suggest nicotine dependence, withdrawal symptoms, and smoking behaviors are heritable up to 60%^116–118. However, no data are available regarding genetic variability in nicotine-mediated organ injury development. Additionally, major nicotine transporters (OCT) expression is highly polymorphic, potentially influencing nicotine distribution across tissues. For instance, meta-analysis showed an association of OCT2 Ser270Ala polymorphism with success of smoking cessation therapy¹¹⁹.

Although there is a clear need to evaluate long-term mechanisms of smoking-associated vascular injury, mechanistic data on post-cessation states as well as animal models of these states are scarce. It is well established clinically that former smokers retain elevated cardiovascular risk for years after quitting³⁰, yet the molecular mechanisms and potential therapeutic targets are unclear. Whether this reflects persistent nitrosative stress, including ONOO⁻-mediated protein modifications and SIRT1 inactivation, sustained eNOS uncoupling driven by residual BH4 depletion, irreversible structural remodeling of the vascular wall, enduring oxidative enzyme upregulation such as Nox5 or iNOS, or epigenetic reprogramming of redox-sensitive pathways have not been mechanistically characterized in post-cessation states. While models of nicotine withdrawal exist¹²⁰, long-term studies of associated tissue damage and cell-specific mechanisms in cardiovascular and renal systems are limited.

Addressing these limitations requires more mechanistically rigorous studies that move beyond generic “redox stress” toward quantitative, compartment-specific definitions of signaling driven by nicotine itself, independent of receptor activation, which will inform therapeutic approaches to nicotine-mediated cardiovascular and renal damage.

Conclusions and future directions

Despite smoking being the leading preventable cause of death which is responsible for 480,000 deaths annually in the U.S.¹²¹, clinical and academic research has historically focused on cigarette and vape components rather than nicotine itself. Nicotine consumption inflicts global damage, targeting almost every major organ of the body and resulting in at least 18 forms of cancer, and acceleration of multiple cardiorenal and vascular pathologies, including atherosclerosis, myocardial infarction, coronary spasm, stroke, aortic aneurysm, peripheral obstructive arterial disease, arrhythmias, hypertensive heart disease, chronic kidney disease, and heart failure^59,122. Nicotine is strongly linked to cardiovascular disease, hypertension, and CKD^16–18, yet its role in cardiovascular and kidney pathology remains poorly understood, and no targeted therapies exist for former smokers. Smoking cessation is the only recommended intervention, yet it has a low success rate and often leads to prolonged, continuous and undocumented nicotine consumption. While quitting significantly reduces associated health risks, approximately 80% of smokers attempting to quit on their own relapse within the first 30 days, and only about 3% remain abstinent at six months¹²³. Furthermore, nicotine-induced chronic injury and prolonged inflammation impair tissue regeneration¹²⁴, while in organs with limited regenerative capacity, such as the kidneys, nicotine-mediated damage is irreversible. Nicotine poses a significant risk in CKD patients; however, no standardized smoking cessation guidelines exist for this population. Most nicotine cessation therapies contain nicotine, and only two FDA-approved options are nicotine-free. There is an urgent need for therapeutic strategies to mitigate persistent nicotine-induced vascular and kidney damage. Further mechanistic studies are essential for their development.

Collectively, the body of work reviewed here establishes nicotine as an active pathogenic driver of cardiovascular and renal injury rather than a benign addictive compound. However, the existing literature is weighted toward vascular mechanisms, with far fewer mechanistic studies interrogating renal parenchymal cells, particularly podocytes and proximal tubules that are directly exposed to filtered nicotine and its metabolites and are central to CKD progression. Even within the cardiovascular field, most studies emphasize nAChR-dependent signaling, while direct, receptor-independent intracellular actions of nicotine (including membrane diffusion and transporter-mediated uptake remain poorly characterized.

Several critical gaps emerge that should shape future research directions. First, there is a striking absence of sex-specific data, despite well-established differences in nicotine metabolism, nitric oxide signaling, mitochondrial biology, and cardio-renal disease susceptibility between males and females. Mechanistic studies in the kidney should move beyond vascular effects to rigorously examine epithelial metabolic pathways, including how nicotine alters bioenergetics, redox buffering, and cell-to-cell crosstalk along the nephron. The pervasive use of the umbrella term “oxidative stress” in the literature has limited mechanistic resolution; future work must distinguish specific reactive species (e.g., superoxide, hydrogen peroxide, peroxynitrite), defined sources (mitochondria, NOX isoforms, uncoupled NOS), and subcellular compartments, as well as temporal dynamics that differentiate adaptive from maladaptive signaling in response to nicotine. Importantly, emerging evidence implicates nitrosative stress and NOS uncoupling, functional drivers of lipid peroxidation, as underappreciated mechanisms of nicotine-induced injury that may be particularly relevant in chronic disease states such as hypertension, diabetes, and CKD. Dissecting how nicotine shifts NO signaling toward peroxynitrite generation, protein nitration, and irreversible metabolic remodeling (independent of receptor activation) represents a high-priority direction. Additional future efforts should include development of post-cessation models that reflect hypertension and CKD development, and incorporation of clinically relevant nicotine dosing paradigms, including nicotine replacement products and passive exposure. Integration of human genetics would be essential to understand interindividual susceptibility to nicotine-induced damage. Finally, identification of therapeutic targets that specifically mitigate nicotine-induced redox and nitrosative tissue injury need to be in the center of attention. Addressing these gaps is essential for moving the field from associative observations to actionable mechanisms and for developing strategies to protect vulnerable cardio-renal populations who remain under risk long after smoking cessation.

ABBREVIATIONS

BH₄

tetrahydrobiopterin

CKD

chronic kidney disease

ESRD

end-stage kidney disease

ETC

electron transport chain

GTPCH1

GTP cyclohydrolase-1

nAChRs

nicotinic acetylcholine receptors

NNN

N-Nitrosonornicotine

NNK

Nicotine-derived nitrosamine ketone

NOX

NADPH oxidase

NRP

nicotine-replacement products

OCT

organic cation transporters

RNS

reactive nitrogen species

SRNG

smoking-related nodular glomerulopathy

TSNAs

tobacco-specific nitrosamines

VSMC

vascular smooth muscle cells

DATA AVAILABILITY STATEMENT.

There is no data associated with this review manuscript.