Nicotine signaling and progression of chronic kidney disease in smokers

Abstract

The deleterious health effects of cigarette smoking are far reaching, and it remains the most important modifiable risk factor for improving overall morbidity and mortality. In addition to being a risk factor for cancer, cardiovascular disease and lung disease, there is strong evidence, both from human and animal studies, demonstrating a role for cigarette smoking in the progression of chronic kidney disease (CKD). Clinical studies have shown a strong correlation between cigarette smoking and worsening CKD in patients with diabetes, hypertension, polycystic kidney disease, and post kidney transplant. Nicotine, in addition to its role in the addictive properties of cigarette smoking, has other biological effects via activation of non-neuronal nicotinic acetylcholine receptors (nAChRs). Several nAChR subunits are expressed in the normal kidney and blockade of the α7-nAChR subunit ameliorates the effects of nicotine in animal models of CKD. Nicotine increases the severity of renal injury in animal models including acute kidney injury, diabetes, acute nephritis and subtotal nephrectomy. The renal effects of nicotine are also linked to increased generation of reactive oxygen species and activation of pro-fibrotic pathways. In humans, nicotine induces transitory increases in blood pressure accompanied by reductions in glomerular filtration rate and effective renal plasma flow. In summary, clinical and experimental evidence indicate that nicotine is at least in part responsible for the deleterious effects of cigarette smoking in the progression of CKD. The mechanisms involved are the subject of active investigation and may result in novel strategies to ameliorate the effects of cigarette smoking in CKD.

Hypoxia: The Force that Drives Chronic Kidney Disease

“…21,25 In addition, nicotine binds a range of nicotinic acetylcholine receptors expressed by mesangial, endothelial, vascular smooth muscle, and renal proximal and distal tubule cells. [195][196][197][198] These receptors are expressed under normoxic conditions but are induced by both transient and chronic hypoxia. 199,200 Upon nicotine binding, receptors mediate activation of protein kinase C that in turn activates nicotinamide adenine dinucleotide phosphate-oxidase to produce reactive oxygen species.…”

“…199,200 Upon nicotine binding, receptors mediate activation of protein kinase C that in turn activates nicotinamide adenine dinucleotide phosphate-oxidase to produce reactive oxygen species. 195,196,[201][202][203][204] Stable compounds within cigarette smoke, such as acrolein, also induce endothelial production of reactive oxygen species through activation of nicotinamide adenine dinucleotide phosphate-oxidase. 205 These oxygen species then act in the same way as those generated through hypertension and hyperglycemia to drive renal hypoxia and kidney damage.…”

“…In addition, the reactive oxygen species produced in response to nicotine also induces mesangial cell proliferation and extracellular matrix deposition through pathways that involve increased expression of cyclooxygenase 2-derived prostaglandins and increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2, c-Jun N-terminal kinases, activator protein 1, and protein kinase B. 195,196,204,[206][207][208][209][210] This aberrant proliferation and deposition mirrors the protein kinase C dependent processes by which hyperglycemia constricts glomerular arterioles to limit blood flow and, hence, oxygen delivery to the kidney. In an additional mirror of hyperglycemia, nicotine also promotes hypoxia by facilitating oxygen-consuming inflammation.…”

Gene Expression Analysis in Tubule Interstitial Compartments Reveals Candidate Agents for IgA Nephropathy

“…Potent evidence showed that human mesangial cells possess the neuronal nicotinic acetylcholine receptors (nAChRs) [26]. The expression of nAChRs subunits promotes the nicotine effect on activating pro-fibrotic pathways, reducing glomerular filtration rate and glomerular filtration rate [27]. Accordingly, response to organic substance is a significant biological process in the development of kidney disease.…”

Nicotine Exposure Augments Renal Toxicity of 5-azacytidine Through p66shc: Prevention by Resveratrol

“…Previously we reported that the anticancer agent 5-aza-cytidine (AZA) elicits oxidative stress-mediated toxicity in cultured renal proximal tubule cells via transcriptional upregulation of the prooxidant p66shc gene and consequent increase in mitochondrial reactive oxygen species (ROS) release (2). Studies revealed that smoking augments severity and progression of renal diseases in humans (3) and in various animal models (4)(5)(6). However, there are no data available on whether smoking could affect renal toxicity of anticancer agents.…”