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Oxidative stress and kidney injury
Reactive oxygen species
Free radicals are chemical species with a single unpaired electron on an outer orbital
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Reactive oxygen species (ROS)
are a type of oxygen derived free radical
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In this process, molecular oxygen is sequentially reduced
in mitochondria by the addition of four electrons to generate water/ during this reaction ROS
and other intermediates are formed, including superoxide anion
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Hydrogen peroxide is much more
stable than superoxide anion
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ROS in leukocytes are generated in a process called
respiratory burst
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Hydrogen peroxide is then
converted to a highly reactive compound hypochlorite by the enzyme myeloperoxidase
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In addition, free radicals are inherently unstable and decay spontaneously
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These situations result in high amounts of superoxide anion
being produced, overwhelming antioxidant enzyme capabilities, thus hydrogen peroxide is
converted to the highly reactive hydroxyl radical, instead of being broken down
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The kidney
The most superficial region of the kidney is the renal cortex
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The cortex is composed of nephrons
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The pyramids are formed of parallel bundles of urine collecting tubules and capillaries
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Nephrons are the structural and functional units of the kidneys
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The loop of Henle is responsible for concentration of urine, through the action of
countercurrent mechanisms
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The kidneys have a high oxygen concentration due to
transport, as such the kidneys receive 20% of the cardiac output
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Kidney disease
In kidney disease there is; a reduction in renal excretory function (uraemia, and drug toxicity
result), an inability to maintain water-electrolyte balance and acid-base balance (metabolic
consequences result), and reduced hormone function (anaemia and hypertension result)
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Ultimately, renal function must be supplemented
artificially, either by dialysis or by a transplanted kidney
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AKI is potentially
reversible
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CKD is generally irreversible
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Renal ischaemia-reperfusion injury
Ischaemia is a low oxygen state usually due to obstruction of arterial blood supply or
inadequate blood flow
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Hypoxia results in
altered metabolic activity, such as reduced ATP formation, activation of transcription factors,
and a reduction in antioxidant enzyme activity
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Reperfusion is the restoration of blood flow, and therefore oxygen, to an organ or tissue
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Renal perfusion is the return
of blood supply to the kidney after a period of ischemia
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However, under certain circumstances, the restoration of blood flow to ischaemic but viable
tissues results in the death of cells that are not otherwise irreversibly injured
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I-R injury may be due to new damage initiated during
reoxygenation by increased generation of ROS from parenchymal and endothelial cells and
from infiltrating leukocytes
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Cellular antioxidant defense mechanisms
may also be compromised by ischemia, favoring the accumulation of free radicals
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Agents which can improve blood flow to the kidney after ischemia include; atrial natriuretic
factor, low dose dopamine, endothelin receptor antagonists, and platelet aggregating factor
antagonist
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Recombinant superoxide dismutase to treat renal ischaemia perfusion injury
SOD was proposed as a pharmacological treatment of I-R injury
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The main reason that
SOD is not in clinical use is the problem of the oxidant-antioxidant balance
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SOD was very protective up to a point beyond which
protection was lost and injury was even exacerbated, with increased lipid peroxidation
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Thus, life for mammalian
cells may be restricted to a narrow window of SOD concentrations where there is enough
SOD to largely suppress superoxide anion dependent initiation events, but not so much as to
completely suppress superoxide dependent termination events
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Small synthetic molecules can mimic the effects of SOD
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Examples of SOD mimetics include;
MnTBAP, MnTMPyP, M40401, EUK-8, and EUK-134
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TEMPOL has
good pharmacological properties as it is; water soluble and relatively stable
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To test
TEMPOL’s activity, isolated and cultures rat proximal tubule cells were grown to confluence
for 7-10 days, the cells were then incubated with increasing concentrations of hydrogen
peroxide for 24 hours and hydroxyl radicals were formed, these cells represent the control
groups, another group of cells were incubated with both increasing concentrations of
hydrogen peroxide and increasing concentrations of TEMPOL
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TEMPOL significantly increased cell viability up to

concentrations of 3mM, however at 10mM TEMPOL significantly decreased cell viability
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TEMPOL was then administered to rat
kidneys in the experimental group
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Renal injury was assessed via histological analysis
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TEMPOL
significantly reduced serum creatinine
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Other interventions to renal I-R injury
Other interventions to treat I-R injury include promoting an increase in the expression or
activity endogenous antioxidant enzymes which may be downregulated during renal I-R, eg
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Another intervention may be to promote an increase in the
expression or activity of other endogenous protective enzymes such as heme oxygenase
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An
alternate intervention is preconditioning
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Preconditioning may be chemical or pharmacological, for example
using lipopolysaccharide, or ischaemic whereby repeated short episodes of ischaemia
protect against a subsequent ischaemic insult
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Diabetic kidney disease is characterised by; mesangial
expansion, glomerular hypertrophy, diffuse glomerulosclerosis, nephrotic syndrome, and a
decline in renal function
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It takes 25-30 years for the kidneys to progress to end stage
renal disease
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Current
treatments aim to prevent or delay diabetic kidney disease by controlling hypertension and
hyperglycemia
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The rate of progression of diabetic kidney disease is accelerated in the later
stages
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Hyperglycemia induced excess superoxide inhibits the glycolytic enzyme
GAPDH, the enzyme required for the conversion of glyceraldehyde-3-phosphate to
1,3-diphosphoglycerate in the metabolism of glucose
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This results in increased
flux of dihydroxyacetone phosphate (DHAP) to DAG, an activator of protein kinase C(PKC),
and or triose phosphates to methylglyoxal, the main intracellular advanced glycation end
(AGE) precursor
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the polyol,

hexosamine, PKC, and AGE pathway all produce superoxide anion, and are all upregulated
by hyperglycemia induced superoxide anion overexpression
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The PKC pathway, which is promoted
by hyperglycemia, can result in vasoconstriction of blood vessels in the kidney, renal cell
overgrowth, renal inflammation, oxidant injury to podocytes and other renal cells
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In a small
clinical trial involving 123 diabteic patients with microalbuminuria, daily ruboxistaurin
treatment was shown to reduce albuminuria by 24%
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SGLT2 inhibitors for treatment of diabetic kidney disease
SGLT2 inhibitors inhibit subtype 2 of the sodium-glucose transport protein
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Thus, inhibition of SGLT2, prevents reabsorption of glucose from the filtrate
back into the blood, and the glucose is instead excreted in the urine
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Examples of SGLT2 inhibitors include; Dapagliflozin (Farxiga), Canagliflozin
(Invokana), Lipragliflozin, and Topogflozin
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However, these side effects
are outweighed by the risk of diabteic complications
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Thus SGLT2 may have possible antioxidant properties

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