Chronic nicotine exposure exacerbates acute renal ischemic injury

Abstract

Recent epidemiological reports showed that smoking has a negative impact on renal function and elevates the renal risk not only in the renal patient but perhaps also in the healthy population. Studies suggested that nicotine, a major tobacco alkaloid, links smoking to renal dysfunction. While several studies showed that smoking/chronic nicotine exposure exacerbates the progression of chronic renal diseases, its impact on acute kidney injury is virtually unknown. Here, we studied the effects of chronic nicotine exposure on acute renal ischemic injury. We found that chronic nicotine exposure increased the extent of renal injury induced by warm ischemia-reperfusion as evidenced by morphological changes, increase in plasma creatinine level, and kidney injury molecule-1 expression. We also found that chronic nicotine exposure elevated markers of oxidative stress such as nitrotyrosine as well as malondialdehyde. Interestingly, chronic nicotine exposure alone increased oxidative stress and injury in the kidney without morphological alterations. Chronic nicotine treatment not only increased reactive oxygen species (ROS) production and injury but also exacerbated oxidative stress-induced ROS generation through NADPH oxidase and mitochondria in cultured renal proximal tubule cells. The resultant oxidative stress provoked injury through JNK-mediated activation of the activator protein (AP)-1 transcription factor in vitro. This mechanism might exist in vivo as phosphorylation of JNK and its downstream target c-jun, a component of the AP-1 transcription factor, is elevated in the ischemic kidneys exposed to chronic nicotine. Our results imply that smoking may sensitize the kidney to ischemic insults and perhaps facilitates progression of acute kidney injury to chronic kidney injury.

Thromboembolic injury and systemic toxicity induced by nicotine in mice

“…However, Arany et al (2011) found that chronic nicotine exposure increased the extent of renal injury which may be attributed to their prolonged treatment for 4 weeks. Similarly, measurement of BUN showed no significant changes which is in contrary to the finding of Sener et al (2005) who show a significant increase in the BUN values.…”

Cigarette smoking and chronic kidney diseases

“…39 Chronic exposure to nicotine exacerbates the acute renal ischemic injury. 40 These reports strongly suggest that the causative agent for CKD in cigarettes is nicotine (Figure 2). …”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…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.…”