Page 309 - Read Online

Cervantes-Gracia et al. Vessel Plus 2020;4:27 I http://dx.doi.org/10.20517/2574-1209.2020.22 Page 7 of 19

Antioxidant defense mechanisms decrease with age [123] , therefore age is a major risk factor of CIN. The
unique anatomy of the renal medulla requires the thick ascending limbs of the loop of Henle to carry out
energetically challenging ion transport in a state of relative hypoxia compared to the renal cortex. It has
been proposed that a discrepancy between the metabolic requirements of these thick ascending limbs
and the medullary blood supply could generate O 2 [124] . The thick ascending limb is associated with ROS
generation mostly due to the extremely high mitochondrial density and therefore, mitochondrial ROS
generation [125] . Reduced renal blood flow can induce oxidative stress and osmotic necrosis consequently
generating ROS, via a positive feedback mechanism, leading to acute tubular necrosis [114,123] . Renal
microcirculation is compromised by ROS production, which affects renal vascular function by facilitating
the production of vasoconstrictors such as endothelin-1 and ameliorating the effects of vasodilators, such
as NO [126] . Direct toxicity of CM in renal tubular cells can also result in mitochondrial dysfunction and,
combined with elevated levels of ROS, leads to extensive damage of glomerular cells by compromising the
[127]
cellular membrane, ultimately resulting in apoptosis .
A crucial factor in the production of ROS in the kidney is renal hypoxia. There are, however, conflicting
reports relating to the extent to which oxidative stress is a cause or epiphenomena. ROS are regularly
involved in cellular inflammatory responses and it is proposed that ROS are formed during renal
parenchymal hypoxia, following CM exposure, resulting in vascular endothelial injury. This aggravates
renal parenchymal hypoxia resulting in endothelial dysfunction [125] . O can lead to the accumulation of
2
-
ONOO , the production of which reduces NO bioavailability. In addition, ROS activate p38 MAPK stress
kinases and c-Jun N-terminal kinases, that are involved in the activation of caspase-3 and caspase-9, which
are associated with the induction of apoptosis [128] . Mitochondrial dysfunction can induce apoptosis by
releasing cytochrome c and activating caspase-9, which in turn activates caspase-3. Caspase-3 plays a major
role in apoptotic signaling by mediating death receptor-dependent and mitochondria-dependent apoptosis
[129]
pathways .
In response to excessive oxidative stress, cells activate/induce their own antioxidant defense mechanisms.
Glutathione (GSH), is an important endogenous thiol that is essential to a variety of detoxification
processes. Mammalian cells contain high concentrations of GSH (3-5 mmol/L) which is used in numerous
diverse roles as well as hepatic detoxification. GSH can donate reducing equivalents for the activity of
specific antioxidant peroxidase enzyme, such as GSH peroxidase (GPx), and can react directly with certain
ROS (e.g., carbonate radical). Intracellular levels of GSH are tightly controlled by the enzymes glutamate-
cysteine ligase and GSH synthase (involved in synthesis), GSH reductase (involved in recycling of oxidized
glutathione back to GSH) and GSH transferases (involved in utilization) [130] . Redox enzymes include
[100]
thioredoxin, catalase, GPx, peroxiredoxins and superoxide dismutase (SOD) .

ROLE OF INFLAMMATION IN CIN/CVD
One of the factors that is central to the prevalence of CIN is chronic inflammation. The role of
inflammation in CIN has been extensively studied and clinical trials in humans and animal models have
been performed to help elucidate this role [131-134] . One of the main features of intravascular iodinated
CM is that it causes vasodilation followed by a prolongation in vasoconstriction [135,136] . The vasodilation/
vasoconstriction occurs in all patients that require a CM procedure, but this effect has not been found to
work alone in the increase of CIN risk among patients. Two additional pathways suggested to promote
this increase are cellular toxicity and elevated urinary viscosity that can cause obstructions through stone
formation .
[137]

Although the global prevalence of CIN does not constitute a public health threat, at risk populations, such
as those suffering from higher presence of infectious diseases, have a higher incidence of inflammation
than populations that are not affected by these diseases [138] . A close relationship between inflammatory