Chronic nicotine exposure and acute kidney injury: new concepts and experimental evidence

Abstract

Although the pathological role of smoking in the development of cardiovascular diseases, cancer [1] or chronic obstructive pulmonary diseases has been widely accepted, its impact on kidney function has only recently been recognized, as reviewed in [2, 3]. Epidemiological studies concluded that smoking is an important remediable risk factor for development of proteinuria [4, 5], progression of diabetic nephropathy [6], evolution of chronic kidney disease (CKD) to end-stage renal disease [7– 9] and graft failure in renal transplant patients [2, 10]. At this moment in time, there is a lack of prospective studies evaluating the role of nicotine abuse as a renal risk factor in patients with primary hypertension or primary renal disease [3]. In spite of the clinical and experimental data, the mechanisms responsible for the reported effects have not yet been fully identified. Although some attention has been paid up till now to the role of smoking in CKD, chronic nicotine-mediated exacerbation of acute kidney injury (AKI) may be an underestimated entity, probably masked by other frequently occurring risk factors such as hypertension, diabetes or obesity. Due to the fact that the current therapeutic array of AKI only consists of supportive care and treatment of the underlying causes and considering the growing evidence on the importance of AKI as a precursor to CKD, the issue of smoking as a risk factor of AKI may warrant more attention. In an interesting paper published in the present issue of Nephrology Dialysis Transplantation [11], Arany et al. investigated in detail the influence of chronic nicotine exposure on the exacerbation of ischaemia-reperfusion-induced oxidative stress and AKI in an in vivo and in vitro mouse model. Based on their previous work [12–15], the authors illustrated nicely that chronic nicotine exposure increased the ischaemia-reperfusion-induced AKI-dependent serine 36 phosphorylation (S36A) and ischaemia-reperfusion-induced AKIdependent renal expression of p66shc. The adaptor protein p66shc is a newly recognized mediator of mitochondrial dysfunction, controlling cellular responses to oxidative stress. The activation of p66shc by oxidative stress is accomplished by the phosphorylation at its Ser36 residue, which facilitates its translocation to the mitochondrial intermembrane space and a H2O2-dependent binding to cytochrome c. The oxidation of cytochrome c results in an excessive generation of reactive oxygen species (ROSs), depolarization of the mitochondria and apoptotic or necrotic death of renal cells through inhibition of the prosurvival epidermal growth factor receptor/ras/MEK/ERK pathway [13, 14]. This paper thus unveils a novel mechanism by which nicotine abuse may be involved in the development of AKI. It broadens our knowledge of the previously described pathways [12–15] and may help us to elucidate the exact link between nicotine and the occurrence of acute/CKD. In previous studies, several potential mediators of smokinginduced renal damage have been discussed, which can be subdivided into non-haemodynamic and haemodynamic mechanisms [3, 16]. Besides the smoking-induced activation of the renin–angiotensin system which is one of the multiple complex and heterogeneous mechanisms, Arany et al. focused in detail on the oxidative stress-dependent Ser36 phosphorylation of p66shc through generation of ROSs, mitochondrial depolarization and consequent injury in cultured proximal tubule cells [11]. This process can be compared with the effects of indoxyl sulphate (IS), a uraemic retention product believed to be involved in the progression of chronic damage, on the p53 pathway [17]. IS is synthesized in the liver from indole, which is generated from tryptophan in dietary proteins by the intestinal flora. As a uraemic toxin, it accumulates in serum and the renal tubules when renal function deteriorates. IS stimulates the expression and phosphorylation of p53 through ROS production [18]. Activation of nuclear factorkappa B (NF-κB) and ROS production in proximal tubular cells are responsible for a reduced renal expression of Klotho in CKD [19], which in turn results in fastened senescence of tubular cells and renal damage. The involvement of IS in renal IN F O C U S