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CHAPTER 92

Oxidants in Progressive Kidney Disease

Sudhir V. Shah
University of Arkansas School for Medical Sciences, Little Rock, Arkansas, USA

Chronic kidney disease (CKD) is a worldwide public There are also studies that have examined the role of oxi-
health problem with a rising incidence and prevalence dants and iron in models of progressive renal disease. In this
affecting approximately 10% of the U.S. adult population review I dene the term reactive oxygen metabolites, or oxi-
(Table 1) (96). Chronic renal insufciency, once estab- dants, briey recount the sequence of events that led to the
lished, tends to progress to end-stage renal disease (ESRD). consideration of these metabolites as important mediators of
The number of patients receiving treatment for ESRD in tissue injury, and present the available evidence in support of
the United States has doubled in the past decade with the role of oxidants in both diabetic and nondiabetic glo-
431,128 patients receiving ESRD therapy, a number ex- merular disease and their role in tubular interstitial damage
pected to increase to 2 million by year 2030 (132). The which accompanies progression.
total estimated cost for Medicare patients with ESRD is Oxygen normally accepts four electrons and is converted
currently $15.48 billion, consuming 6.4% of the Medicare directly to water. However, partial reduction of oxygen can
budget (132), and is forecasted to increase to $28.3 billion and does occur in biological systems, which leads to the
by 2010 (146). In addition, there is a high prevalence generation of partially reduced and potentially toxic reactive
of cardiovascular disease in subjects with CKD. The oxygen intermediates (35, 82). Thus sequential reduction of
American Heart Associations Councils on Kidney in oxygen along the univalent pathway leads to the generation
Cardiovascular Disease, High Blood Pressure Research, of superoxide anion, hydrogen peroxide, hydroxyl radical,
Clinical Cardiology, and Epidemiology and Prevention, in and water (35, 82).
a statement entitled, Kidney Disease as a Risk Factor for
Development of Cardiovascular Disease, concluded that the Oxygen superoxide hydrogen peroxide hydroxyl radical water
presence of CKD, whether it is manifested by proteinuria (free radical) (free radical)
(albuminuria) or reduced GFR [glomerular ltration
(Eq. 1)
rate], appears to be an independent risk factor for CVD
[cardiovascular disease] outcomes, particularly in higher- Superoxide and hydrogen peroxide appear to be the pri-
risk populations (118). Progression of renal failure occurs mary species generated; they may play a role in the genera-
even when the primary disease process has been treated or tion of additional and more reactive oxidants, including the
is apparently inactive, indicating that the alterations and highly reactive hydroxyl radical (or a related highly oxidizing
adaptations in nephrons that remain after the initial insult species) in which iron salts act as a catalyst in a reaction
ultimately cause scarring and further nephron loss, which commonly referred to as the metal-catalyzed Haber-Weiss
result in the end-stage kidney. The overall impact of CKD reaction (49).
is summarized in Table 2.
Although various mechanisms have been suggested to Fe 3 O 2 Fe 2 O 2
promote progressive renal injury (31), in this chapter I will Fe 2 H 2 O 2 Fe 3 OH OH
focus on partially reduced oxygen metabolites, which have
been shown to be important mediators of ischemic, toxic,
O 2 H 2 O 2 O 2 OH OH
and immune-mediated tissue injury (9, 23, 33, 34, 81, 143).
Numerous studies have examined the role of reactive oxygen
(Eq. 2)
metabolites in leukocyte-dependent and -independent mod-
els, with proteinuria as a major endpoint. To the extent that Iron, a transitional metal, can serve as a carrier for oxygen
proteinuria is an important determinant of progression, re- and electrons and a catalyst for oxygenation, hydroxylation,
duction of proteinuria would result in retardation of pro- and other critical metabolic processes, in part because of its
gression. In addition, evidence suggests a role of oxidants ability to reversibly and readily cycle between the ferrous
and iron in diabetic nephropathy, a major cause of ESRD. and ferric oxidation states. The ease with which iron is

Copyright 2008, Elsevier Inc.


Seldin and Giebischs The Kidney 2601 All rights reserved.
2602 SECTION IV Progression of Renal Disease

TABLE 1 Stages of Chronic Kidney Disease and Prevalence in the Adult U.S.
Population
Stage Description GFR (ml/min/1.73 m2) Population %
1 Kidney damage with normal or GFR 90 5.9 million 3.3
2 Kidney damage with mild GFR 6089 5.3 million 3.0
3 Moderate GFR 3059 7.6 million 4.3
4 Severe GFR 1529 400,000 0.2
5 Kidney failure 15 (or dialysis) 300,000 0.2
19.2 million 11

GFR, glomerular ltration rate.


Source: National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evalu-
ation, classication, and stratication. Part IV: denition and classication of stages of chronic kidney disease.
Am J Kid Dis. 2002;39(2 Suppl 1):S46S75.

reversibly oxidized and reduced is essential for its metabolic hydrogen peroxide can release iron by degrading heme
functions. However, this property makes iron potentially proteins (49).
hazardous by enabling it to participate in the generation of Additional reactive oxygen metabolites are formed as a
such powerful oxidant species as hydroxyl radical and/or result of the metabolism of hydrogen peroxide by
reactive ironoxygen complexes such as ferryl or perferryl neutrophil-derived myeloperoxidase (MPOthe enzyme
ion (49). responsible for the green color of pus) to produce highly
Iron also has a major role in the initiation and propaga- reactive toxic products including hypochlorous acid. MPO
tion of lipid peroxidation by catalyzing the conversion of reacting with hydrogen peroxide forms an enzyme sub-
primary oxygen radicals to hydroxyl radicals or forming a strate complex that can oxidize various halides to produce
perferryl ion. In addition, iron can directly catalyze lipid highly reactive toxic products. Because of the wide distri-
peroxidation, the oxidative reaction of polyunsaturated bution of chloride ion in biologic systems, the formation
lipids, by removing hydrogen atoms from the polyunsatu- of hypochlorous acid (HOClthe active ingredient in
rated fatty acids in the lipid bilayers of organelle mem- Clorox bleach) is probably te most signicant product (33,
branes. An important feature of lipid peroxidation is that 69, 74, 144).
the process can amplify the production of free radicals and
thus increase the number of chain reactions. Other reac- H 2 O 2  Cl MPO
HOCl  H 2 O
tions in which the effect of iron catalysts is to convert The reader is referred to an excellent review that details
poor reactive species into more reactive species are well the various products including tyrosyl radical adduction
described in the excellent review by Halliwell and Gut- products, resulting from the MPO-hydrogen peroxide-
teridge (49). chloride system, as well as the potential role in kidney
Because iron can participate in the formation of reac- disease (78). These oxygen metabolites, including the free
tive oxygen species, organisms take great care in the han- radical species superoxide and hydroxyl radical and other
dling of iron, using such transport proteins as transferrin metabolites such as hydrogen peroxide and hypohalous
and such storage proteins as ferritin and minimizing the acids, are often referred to collectively as reactive oxygen
size of the intracellular iron pool. The availability of iron metabolites or reactive oxygen species, or simply as
to stimulate hydroxyl generation in vivo is very limited oxidants.
under normal conditions; this iron sequestration may be It is now well established that oxidants generated by
regarded as a contribution to antioxidant defenses. Al- leukocytes have bactericidal activity, which indicates at
though there has been much debate about the availability least one functional role for oxidants (5). The notion that
of catalytic metal ions in vivo, it is well established that oxidants are important in inammation was rst suggested
oxidant stress itself can provide the catalytic iron. For ex- by McCord. He reasoned that, because phagocytizing neu-
ample, superoxide can mobilize iron from ferritin and trophils, the effector cells of the acute inammatory re-
sponse, release large amounts of superoxide extracellularly
and because superoxide dismutase, an enzyme that scav-
enges superoxide, possesses anti-inammatory activity, su-
TABLE 2 Impact of Chronic Kidney Disease
peroxide anion and other oxygen metabolites could be
Affects about 10% of the population important chemical mediators of the inammatory process
Progressive, culminating in end-stage kidney disease (80). This hypothesis has received considerable support
Enormous human and economic cost
from numerous studies in which the effect of oxidants,
Independent risk factor for cardiovascular disease
produced either by an enzymatic-generating system or by
CHAPTER 92 Oxidants in Progressive Kidney Disease 2603

activated leukocytes, has been examined in a variety of bio- mune complexes, and complement components have been
logical systems as well as in vivo studies, where scavengers shown to trigger the oxidative burst (33). Antineutrophil
of oxidants are protective. cytoplasmic autoantibodies (ANCAs) present in the circula-
tion of patients with pauci-immune necrotizing vasculitis
and pauci-immune crescentic glomerulonephritis have been
ROLE OF OXIDANTS IN NONDIABETIC shown to signicantly increase the generation of superoxide
GLOMERULAR DISEASE by neutrophils (32). Thus stimulated neutrophils or mono-
cytes are potential sources of oxidants in leukocyte-
The evidence implicating oxidants in glomerular injury may dependent glomerular injury. More direct evidence support-
be addressed by three broad questions. What are the sources ing this concept has been given by Poelstra et al., who used
of oxidants that may participate in glomerular injury? What cytochemical techniques to demonstrate the presence of
are the biological effects of oxidants relevant to glomerular superoxide anion and hydrogen peroxide-generating leuko-
pathophysiology? How well has the role of oxidants been cytes in antiThy-1 and anti-glomerular basement mem-
demonstrated in animal models of glomerular disease? brane (GBM)-induced glomerulonephritis (105). Similarly,
enhanced generation of oxidants by macrophages isolated
from glomeruli of rabbits with anti-GBM antibody disease
Sources of Oxidants
and by macrophages isolated from nephritic glomeruli in the
Neutrophils and monocytes/macrophages exhibit a burst of antithymocyte serum model has been demonstrated (17,
oxidative metabolism (respiratory burst), with a marked in- 99). Thus stimulated neutrophils or monocytes may serve as
crease in oxygen uptake and a generation of oxidants in re- sources of oxidants in proliferative and exudative glomerulo-
sponse to plasma membrane perturbation by a variety of nephritides (Table 3).
soluble and particulate stimuli (33). Phagocytosis per se is Ample evidence supports the concept that resident
not essential to trigger the oxidative burst; perturbation of glomerular cells serve as sources of oxidants in noninam-
the plasma membrane appears to be the critical event. In in matory forms of glomerular disease (Table 3). Because
vitro studies, a variety of soluble and particulate stimuli, phagocyte-like cells are present in the glomerulus
many of them relevant to glomerular injury, enhance the (particularly mesangial cells), it was postulated that glo-
generation of oxidants by neutrophils and monocytes. Of merular cells, like other phagocytic cells, would also gen-
particular interest is the demonstration that several immune erate oxidants in response to plasma membrane perturba-
reactants such as serum-treated zymosan (a C3b receptor tion. In response to phorbol myristate acetate, a plasma
stimulus), heat-aggregated IgG (Fc receptor stimulus), im- membrane-perturbing agent, rat glomeruli showed a

TABLE 3 Leukocytes as a Source of Oxidants for Glomerular


Injury
In vitro studies
o A wide variety of soluble and particulate stimuli, including immune complexes,
complement components, (30) and ANCA (21)
In vivo studies
o Cytochemical detection of the presence of superoxide- and hydrogen peroxide-
generating leukocytes in anti-Thy-1 and anti-GBM-induced GN (22)
o Enhanced superoxide and hydroxyl radical are generated by macrophages isolated
from glomeruli of rabbits with anti-GBM antibody disease (23)
o Enhanced superoxide generation by macrophages isolated from nephritic glomeruli
(antithymocyte serum) (24)

Resident glomerular cells as a source of oxidants for glomerular injury


In vitro studies (150)
o Isolated glomeruli Phorbol myristate acetate, zymosan, trypsin,
ehymotrypsin, adriamycin
o Mesangial cells PAF, immune complexes, MAC, TNF,
interleukin-1
o Glomerular epithelial cells Puromycin aminonucleoside
In vivo studies
o Production of hydrogen peroxide by normal rat kidney glomeruli (151)
o Increased generation of hydrogen peroxide in passive Heymann nephritis (152)

ANCA, antineutrophil cytoplasmic autoantibody; GBM, glomerular basement mem-


brane; GN, glomerulonephritis.
2604 SECTION IV Progression of Renal Disease

marked chemiluminescence response, a sensitive measure EFFECTS OF OXIDANTS RELEVANT TO PROTEINURIA


of oxidants generated by phagocytic cells. In a subsequent It is generally accepted that leukocytes cause proteinuria
study, chymotrypsin or trypsin markedly increased light (a hallmark of glomerular diseases) by damaging the GBM,
emission from the glomeruli. Neutral proteases from inl- which serves as the major ultraltration barrier to restrict the
trating leukocytes and/or renal tissue are released in glo- entry of proteins into the urinary space. The degradation of
merular diseases, which suggest a potential mechanism for the GBM by stimulated neutrophils is caused by the activa-
the production of oxidants in glomerular diseases. In vivo tion of a latent metalloenzyme (most likely gelatinase)
generation of hydrogen peroxide by normal glomeruli has by hypochlorous acid or a similar oxidant generated by the
been demonstrated using aminotriazole-induced inactiva- myleoperoxidase-hydrogen peroxide-halide system (Table 4)
tion of catalase as a measure of intracellular generation of (126). Other studies have shown that oxidants could contrib-
hydrogen peroxide (40). Adriamycin, an agent that in- ute to GBM damage by increasing its susceptibility to pro-
duces nephrotic syndrome, has been shown to enhance the teolytic damage (142) and by inactivating the 1-proteinase
intracellular generation of oxidants by freshly isolated inhibitor (the primary regulator of neutrophil elastase) (145),
glomeruli in vitro (140). thus allowing the released elastase to more readily inict
These studies with isolated glomeruli are supported by damage to the extracellular matrix. Lipid peroxide enhances
studies using cultured glomerular cells. Mesangial cells have the production of gelatinase by mesangial cells, and thus
enhanced generation of superoxide and hydrogen peroxide enhanced generation of matrix-degrading proteinase may
in response to a variety of stimuli, including opsonized contribute to proteinuria (64). Prevention of proteinuria by
zymosan, immune complexes, membrane attack complex, catalase in neutrophil-dependent glomerulonephritides (vide
and platelet-activating factor (11, 108, 125). Radeke et al. infra) suggests that the oxidative mechanism for GBM deg-
showed that human glomerular mesangial cells express radation described above may be relevant to leukocyte-
low potential cytochrome b558  and  subunits, a 45- or dependent glomerular injury.
66-kD avoprotein, and a 47-kD phosphoprotein, the three In contrast to the increased degradation suggested by
essential components of a plasma membrane-associated these studies, Kanwar et al. suggest that synthesis of glo-
NADPH (nicotinamide adenine dinucleotide phosphate) merular heparan sulfate proteoglycans (HSPGs) is highly
oxidase system, in a manner similar to that described in susceptible to oxidant injury (66). A drastic dose-dependent
neutrophils (107). Finally, glomerular epithelial cells appear decrease in the de novo synthesis of proteoglycans in re-
to be the target of injury in many of the noninammatory sponse to xanthine-xanthine oxidase (a system that gener-
forms of glomerular disease, including nephrotic syndrome ates oxidants) was demonstrated using an isolated perfused
induced by the injection of puromycin aminonucleoside. kidney model. Morphological studies revealed a marked
In response to puromycin aminonucleoside, cultured glo- decrease in the synthesis of the proteoglycan. Thus the na-
merular epithelial cells enhance the generation of hydrogen scent core peptide appears to be highly susceptible to selec-
peroxide (67). The ability of glomerular cells to generate tive direct damage from oxidants during de novo synthesis
oxidants appears to be well established (Table 3). Therefore, of HSPGs necessary to maintain integrity of the GBM and
either leukocytes in inammatory glomerular diseases or normal glomerular ultraltration.
resident glomerular cells in noninammatory diseases serve Direct in vivo effects of oxidants on glomerular function
as sources for oxidants. have been examined in several studies (Table 4). Infusion of
phorbol myristate acetate (a potent activator of leukocytes)
or of cobra venom factor in the renal artery caused signi-
Effects of Oxidants Relevant to Glomerular Disease
cant proteinuria that was prevented by catalase (which
The major manifestations of glomerular disease are protein- destroys hydrogen peroxide) and neutrophil depletion (111,
uria, altered glomerular ltration rate (GFR), and depend- 113, 148). It was shown that hydrogen peroxide infused
ing on the type of glomerular disease, morphological changes directly into the renal artery caused massive transient pro-
(Fig. 1). The biological effects of oxidants have been divided teinuria with no effect on GFR and renal plasma ow (149).
into three general areas: those that are most relevant to the Fraction clearances of graded-size neutral dextrans of larger
occurrence of proteinuria, those that are most relevant to molecular radii, an index of glomerular size selectivity, were
altered GFR, and those that are most relevant to morpho- signicantly and substantially elevated after hydrogen per-
logical changes. oxide infusion.
These studies indicate that hydrogen peroxide and/or
its metabolites generated by neutrophils can cause protein-
uria. Johnson et al. reasoned that hydrogen peroxide-
mediated injury involves the myeloperoxidase-hydrogen
peroxide-halide system. The postulate is particularly
attractive in view of the high cationic nature of myeloper-
FIGURE 1 The role of random oxygen metabolites (ROM) in glo- oxidase with an isoelectric point above 10. Johnson et al.
merular disease. The major manifestations of glomerular disease. demonstrated that infusion of myeloperoxidase followed
CHAPTER 92 Oxidants in Progressive Kidney Disease 2605

TABLE 4 Effects of Oxidants Relevant to Occurrence of Proteinuria


in Glomerular Injury
Oxidants participate in glomerular basement membrane degradation (33, 34).
Lipid peroxide induces enhanced generation of gelatinase by mesangial cells (36).
Oxidants decrease de novo synthesis of glomerular proteoglycans (37).
Oxidants increase albumin permeability in freshly isolated glomeruli in vitro (153).
Direct in vivo effects of oxidants on urinary protein
Infusion of phorbol myristate acetate, an activator of neutrophils, results in proteinuria (38) and
a fall in glomerular ltration rate (40). These effects are prevented by a catalase.
Hydrogen peroxide infused directly into the renal artery causes massive transient proteinuria by
inducing a molecular size selectivity defect (41). These effects are prevented by an iron chelator.
Infusion of myeloperoxidase-hydrogen peroxide induces proteinuria (42).

by hydrogen peroxide in a chloride-containing solution the observed effects of oxidants may be mediated through
into the renal artery in rats results in signicant proteinuria their effect on prostaglandin and thromboxane synthesis.
(62) and, 4 to 10 days later, development of a marked Roberts et al. identied a series of prostaglandin F2-like
proliferative glomerular lesion (Table 4) (63). In addition, compounds that are produced in vivo in humans by a non-
halogenation of glomeruli was demonstrated in an in situ cyclooxygenase mechanism involving free radical-catalyzed
model of neutrophil-mediated immune complex glomeru- peroxidation of arachidonic acid (87). Intrarenal arterial in-
lonephritis (62). These studies indicate that the myeloper- fusion of small amounts (0.5 g/kg/min) of 8-epi-PGF2
oxidase-hydrogen peroxide-halide system is activated in resulted in a dose-dependent reduction in GFR and renal
a model of neutrophil-mediated immune complex glo- plasma ow (133). The changes were completely reversed by
merulonephritis and that the myeloperoxidase-hydrogen thromboxane A2 receptor antagonist, which indicates that
peroxide-halide system is capable of inducing glomerular 8-epi-PGF2 is a potent preglomerular vasoconstrictor act-
injury that results in proteinuria. ing principally through thromboxane A2 receptor activation.
This nding suggests that in those glomerular injuries
EFFECTS OF OXIDANTS RELEVANT TO ALTERED GFR where free radical mechanisms, including lipid peroxidation,
Increased production of prostaglandins and thrombox- have been implicated, the formation of novel prostanoids
ane has been demonstrated in various human and experi- plays an important role in the fall in the GFR and the al-
mental glomerulopathies and these agents have been impli- terations in renal plasma ow (RPF) (Table 5). Infusion of
cated as important mediators that cause proteinuria and/or dibutryl cAMP (cyclic adenosine 3 ,5 -cyclic phosphate)
a fall in GFR in experimental models of glomerular disease, and several hormones that increase cAMP content in glom-
including anti-GBM antibody disease, adriamycin-induced eruli cause a fall in the glomerular ultraltration coefcient
nephrotic syndrome in rats, and complement-mediated (30). In addition, the cAMP content in glomeruli is altered
glomerular injury (24, 76, 115). Because the most dramatic most strikingly by several local mediators of inammation
effect of these autocoids is on glomerular hemodynamics, such as serotonin, histamine, and prostaglandins, which sug-
they are further discussed under the effects of oxidants that gests that, as in other systems, cyclic nucleotides modulate
are relevant to altered GFR. It has been demonstrated that inammatory and/or immune response in glomerular dis-
oxidants generated either enzymatically or by stimulated ease (26, 27). It has been shown that xanthine-xanthine
neutrophils increase the synthesis of prostaglandin E2, oxidase increases cAMP content in freshly isolated glomer-
PGF2, 6ketoPGF1, the stable metabolite of prostacyclin, uli, and the responsible metabolite appears to be hydrogen
and thromboxane B2 (Table 2) (1, 12, 122). Thus some of peroxide (123). Similarly, cell-free supernatants from

TABLE 5 Effect of Oxidants Relevant to Altered GFR in Glomerular


Injury
Oxidants generated enzymatically or by stimulated neutrophils
o Increase glomerular cyclic AMP content (5556)
o Induce a reduction in glomerular and mesangial cell planar surface and myosin light chain
phosphorylation (57)
o Increase glomerular eicosanoid synthesis (4749)
Infusion of 8-epi-PGF2, a novel prostanoid produced by noncyclo-oxygenase mechanism
involving lipid peroxidation (50) results in a marked fall in GFR and RPF (51).

AMP, adenosine monophosphate; GFR, glomerular ltration rate; RPF, renal plasma ow.
2606 SECTION IV Progression of Renal Disease

stimulated neutrophils increase cAMP content in freshly noid necrosis of the GBM and marked inltration of neu-
isolated glomeruli, and this effect appears to be mediated by trophils and mononuclear cells. The close association of
hydrogen peroxide and hypochlorous acid, the product of pauci-immune necrotizing glomerulonephritis and anti-
the myleoperoxidase-hydrogen peroxide-halide system (8). MPO antibodies suggests a pathogenetic role for anti-
It was shown that the xanthine-xanthine oxidase system MPO-directed immune response. Rats immunized with
induced a reduction in the glomerular and mesangial cell MPO and perfused with lysosomal enzyme extract and hy-
planar surface and an increase in myosin light chain phos- drogen peroxide developed glomerular intracapillary throm-
phorylation, a biochemical marker of contraction (28). In- boses, followed by a proliferative glomerulonephritis charac-
terestingly, these effects were completely blocked by a terized by glomerular capillary wall necrosis, extracapillary
platelet-activating factor antagonist, which suggests that the cell proliferation, inltration of neutrophils and monocytes,
effects of oxidants are mediated by platelet-activating factor. and vasculitis (29). These studies indicate that oxidants are
Duque et al. suggest that oxidants, particularly hydrogen capable of inducing many of the functional and morpho-
peroxide, could modulate the surface area of mesangial cells, logical changes that are observed in glomerular diseases.
modifying the ultraltration coefcient, and this change Oxidants have usually been regarded as toxic metabolites
could explain the decrease in the GFR in those pathological with cytotoxic properties. However, at low concentrations
conditions characterized by a fall in GFR. they seem to play a signicant regulatory role without in-
ducing cell death. The effects of oxidants in altering cAMP
EFFECTS OF OXIDANTS RELEVANT levels have been described above. In addition, regulated
TO MORPHOLOGICAL CHANGES generation of low concentrations of oxidants may serve as
Several studies have implicated platelets in glomerular intracellular signals for gene activation involving specic
injury. As mentioned previously, infusion of myleoperoxi- transcription factors such as NF-
B (119, 120, 136) and
dase and hydrogen peroxide causes a marked inux of plate- may represent a second messenger system for generation of
lets, endothelial cell swelling, and epithelial cell foot process cytokines involved in tissue injury and repair. A number of
effacement followed by a marked proliferative glomerular monocyte-specic cytokines have been described that in-
lesion (63). In addition, low doses of hydrogen peroxide clude the monocyte colony-stimulating factor (M-CSF) and
stimulate the proliferation of cultured rat mesangial cells the monocyte chemoattractant protein-1 (MCP-1). MCP-1
(29). These ndings indicate that oxidants are capable of has been identied as a product of a gene belonging to the
inducing morphological changes that are similar to those small, inducible cytokine family, known in the murine sys-
seen in models of immune complex glomerulonephritis and tem as the JE gene. CSF1 is a cytokine required for prolif-
anti-GBM antibody disease. eration, maturation, and activation. Expression of the
It has been suggested that glomerular ADPase is of major JE/MCP-1 and CSF1 genes can be rapidly induced by a
importance in preventing intraglomerular thrombus forma- number of agents, including tumor necrosis factor. Satriano
tion in experimental glomerulonephritis (105). Membrane- et al. have shown that scavengers of free radicals attenuate
associated enzymes are apparently highly susceptible to oxi- the increase in the mRNA level in response to TNF- and
dants (6). There is a marked decrease in the activity of these aggregated IgG. Generation of superoxide anion by xan-
enzymes in two models of glomerulonephritis (anti-GBM thine oxidase and hypoxanthine increases the mRNA levels
and anti-Thy-1) that is characterized by an inux of poly- of these genes. They concluded that the generation of reac-
morphonuclear neutrophils (105). Scavengers of oxygen tive oxygen species, possibly by NADPH-dependent oxi-
metabolites prevent the decrease in glomerular ADPase, dase, is involved in the induction of the JE/MCP-1 and
which suggests that oxidants act in the reduction of glo- CSF-1 genes by TNF- and IgG complexes. Local genera-
merular ADPase activity (Table 6) (105). tion of oxidants could represent a factor responsible for the
Necrotizing crescentic glomerulonephritis associated expression of JE/MCP-1 in immune-mediated increased
with anti-MPO antibodies is part of ANCA-associated expression of monocyte chemoattractant protein in glom-
glomerulonephritis and is characterized by segmental bri- eruli from rats with anti-Thy-1 glomerulonephritis (130).

TABLE 6 Role of Oxidants in the Morphological Changes Relevant


to Glomerular Injury
Infusion of myeloperoxidasehydrogen peroxide causes marked inux of platelets, signi-
cant proteinuria, followed by a marked proliferative glomerular lesion (4243).
Scavengers of oxidants prevent the reduction in glomerular ADPase activity in anti-Th- 1
and anti-glomerular basement membrane antibody disease models (22).
Rats immunized with myeloperoxidase and perfused with lysosomal enzyme extract and
hydrogen peroxide develop a proliferative glomerulonephritis (58).
Oxidants induce JE/MCP-1 and CSF-1 genes by TNF- and IgG complexes in mesangial
cells (154).
CHAPTER 92 Oxidants in Progressive Kidney Disease 2607

Tumor necrosis factor is able to generate oxidants, super- TABLE 8 Evidence for the Role of Oxidants in an
oxide anion, and hydrogen peroxide in glomerular mesan- Animal Model of Minimal Change Disease
gial cells. There is also in vitro evidence of effects of In a puromycin aminonucleoside model of minimal change disease
oxidants on the release of TNF- from lipopolysaccharide- Cultured glomerular epithelial cells exhibit an enhanced generation of
activated mesangial cells (10, 11). Although the role of hydrogen peroxide (32).
these cytokines has not been adequately dened in glo- Administration of scavengers of oxidants and antioxidants results in re-
merular diseases, these results indicate important interac- duction in proteinuria (68, 69, 72, 155).
Glomerular catalytic iron increases (156).
tions between other mediators and reactive oxygen species. Feeding a selenium-decient diet results in a marked diminution of glu-
For additional examples of such interactions, the reader is tathione peroxidase accompanied by an increase in proteinuria (157).
referred to a review (4).

Oxidants in Animal Models of Glomerular Disease


ANTI-GBM ANTIBODY DISEASE protective effect of superoxide dismutase and in addition
One of the best-characterized models of complement- reported that proteinuria was signicantly reduced in rats
and neutrophil-dependent glomerular injury is the heterolo- receiving polyethylene glycol (PEG) catalase, which sug-
gous phase of anti-GBM antibody disease. In this model, gested a role for hydrogen peroxide and superoxide anion
treatment with catalase markedly reduced proteinuria, in this model of glomerular disease (13). Superoxide anion
whereas superoxide dismutase had no protective effect and hydrogen peroxide may interact (with iron as a cata-
(Table 7) (112). In another study, dimethylthiourea, a potent lyst) to generate hydroxyl radical. Several studies have in
hydroxyl radical scavenger, or deferoxamine, an iron chela- fact shown that enhanced generation of hydrogen peroxide
tor, signicantly attenuated proteinuria in the complement- and superoxide anion is accompanied by enhanced genera-
and neutrophil-dependent heterologous phase of anti-GBM tion of a hydroxyl radical (or a similar highly oxidizing
antibody disease in rabbits (16). Although the role of iron is species). Thakur et al. reported the protective effects of two
not completely understood, the protective effect of iron hydroxyl radical scavengers and an iron chelator, further
chelators has generally been taken as evidence for the par- implicating hydroxyl radical in PAN-induced nephrotic
ticipation of hydroxyl radical in tissue injury because iron is syndrome (136).
critical in the generation of hydroxyl radical (via the A single intravenous injection of adriamycin (an anthra-
Haber-Weiss reaction). cycline antibiotic used in cancer chemotherapy) causes
nephrotic syndrome in rats with morphological and func-
ANIMAL MODEL OF MINIMAL CHANGE DISEASE tional changes similar to those seen in minimal change
The ability of glomerular cells to generate oxidants sug- disease in humans (125). Adriamycin undergoes a one-
gests that they may be important mediators of glomerular electron reduction to a free radical, a semiquinone species
injury in glomerular diseases that lack inltrating leuko- catalyzed by microsomes, sarcosomes, mitochondria, nu-
cytes (Table 8). A single intravenous injection of puromy- clei, and cytoplasm (125). Thus adriamycin-induced ne-
cin aminonucleoside (PAN) results in marked proteinuria phrotic syndrome appears to be a good model to demon-
and glomerular morphological changes that are similar to strate the concept that oxidants generated intracellularly by
minimal change disease in humans. Diamond et al. re- glomerular cells can cause glomerular injury resulting in
ported that allopurinol (an inhibitor of xanthine oxidase) proteinuria. However, the evidence from scavenger studies
and superoxide dismutase were protective in PAN-induced is somewhat controversial. One study showed the protec-
nephrotic syndrome, which suggests a role for xanthine tive effect of superoxide dismutase (Table 8) (100), whereas
oxidase-generated superoxide anion in this model of mini- another study did not nd any protective effects of
mal change disease (25). Beaman et al. conrmed the scavengers of oxidants (14).

ANIMAL MODEL OF MEMBRANOUS NEPHROPATHY


Passive Heymann nephritis, induced by a single intrave-
TABLE 7 Evidence for the Role of Oxidants in Anti- nous injection of anti-Fx1A, is a complement-dependent and
GBM Antibody Disease neutrophil-independent model of glomerular disease that re-
In the complement and neutrophil-dependent heterologous phase of sembles membranous nephropathy in humans. Shah reported
anti-GBM antibody disease. that superoxide dismutase or catalase (native or PEG-coupled)
o Anti-GBM enhances generation of oxidants by neutrophils in vitro. did not affect anti-Fx1A-induced proteinuria. In contrast,
o Catalase markedly reduces the proteinuria, whereas superoxide scavengers of hydroxyl radical and deferoxamine markedly re-
dismutase has no protective effect in the heterologous phase (66).
A hydroxyl radical scavenger and an iron chelator signicantly attenuate
duced proteinuria (134). The protective effects of hydroxyl
antiGBM antibodyinduced proteinuria in the heterologous phase (67). radical scavengers and an iron chelator suggest that hydroxyl
radical plays a part in passive Heymann nephritis. Similarly,
GBM, glomerular basement membrane. Rahman et al. reported that two hydroxyl radical scavengers
2608 SECTION IV Progression of Renal Disease

signicantly reduced proteinuria in cationized -globulin- (93), Nishikawa and Brownlee in an article entitled, The
induced immune complex glomerulonephritis, a complement- Missing Link: A Single Unifying Mechanism for Diabetic
and neutrophil-independent model of membranous nephrop- Complications, argue and provide convincing evidence
athy (109). Taken together these studies suggest an important that reactive oxygen metabolites are the causative link
role for hydroxyl radical in animal models of membranous for all the major pathways that have been implicated in
nephropathy (Table 9). diabetic complications.
Although leukocytes have not been considered to be im- Additional support for oxidants in vascular disease of
portant pathogenetically in animal models of membranous diabetes comes from an in vivo study published in the
nephropathy, there is evidence for the potential participation Journal of Clinical Investigation in 2001 (104), where it was
of an MPO-hydrogen-peroxide-chloride system in patients reported that a hydroxyl radical-like species was responsible
with membranous nephropathy (78). Grone et al. demon- for changes in arterial wall proteins in a model of diabetes in
strated staining for hypochlorous-modied epitopes in con- monkeys (Table 10). Iron may play an important role in the
junction with MPO in the GBM (38). Thus it appears that auto-oxidation reactions of glucose leading to the generation
leukocytes or resident glomerular cells serve as sources for of free radicals (86). In addition, it has been shown that
oxidants. In vitro and in vivo studies indicate that oxidants glycation of proteins leads to a substantial increase in the
have many effects that are relevant to functional and mor- afnity for translational metals such as iron and copper
phological changes observed in glomerular injury, and data (106). These glycochelates have the ability to participate in
on scavengers of oxidants document the importance of free-radical reactions. Iron chelators have been shown to
oxidants in glomerular injury. improve coronary artery response to physiological stimuli
and blood ow in diabetes (95).
In addition to these effects on the vascular bed
OXIDANT MECHANISMS IN DIABETES (93, 104, 127), which are likely to be important in the
glomerular vascular bed, there is more direct evidence for
There is a large body of evidence indicating that diabetes oxidants in diabetic nephropathy (19, 42, 56, 68, 110).
is a state of increased oxidative stress (52, 79, 117, 128, The in vitro evidence for the role of oxidants in diabetic
147). This chapter summarizes only the information perti- nephropathy can be summarized as follows: High glucose
nent to diabetic nephropathy. In a paper published in increases production of reactive oxygen species in glo-
Nature (94), Nishikawa et al. state that three seemingly merular cells; reactive oxygen species directly have bio-
independent biochemical pathways are involved in the logical effects relevant to diabetic nephropathy; and anti-
pathogenesis of vascular disease: glucose-induced activa- oxidants reduce the high glucose-induced biological effects
tion of protein kinase C isoforms (61, 71); increased for- (Table 11). High glucose increases the production of reac-
mation of glucose-derived advanced glycation end- tive oxygen species directly via glucose metabolism and
products (18); and increased glucose ux through the auto-oxidation and indirectly through the formation of
aldose reductase pathway (75). The relevance of each of advanced glycation end products (AGEs) and their recep-
these pathways is supported by animal studies in which tor binding (43). In in vitro studies it has been shown that
pathway-specic inhibitors prevent various hyperglycemia- high glucose results in increased generation of reactive
induced abnormalities (18, 60, 102, 129). Hyperglycemia oxygen species by mesangial cells (42, 44). AGEs bind to
increases the production of reactive oxygen species inside receptors for AGE and initiate reactive oxygen species
cultured bovine aortic endothelial cells (36). In their study, production (15, 147). Indeed, AGEs have been shown to
Nishikawa et al. show that normalizing levels of reactive increase intracellular generation of reactive oxygen species
oxygen species prevents glucose-induced activation of in mesangial cells (121). Similarly, it has been shown that
protein kinase C, formation of advanced glycation end- high glucose results in lipid peroxidation in isolated
products, sorbitol accumulation and NF-
B activation glomeruli, which is prevented by hydroxyl radical scaven-
(94). In a review published in Kidney International in 2000 gers (42).
Reactive oxygen species can activate most of the known
signal transduction pathways (135). In diabetes, protein
TABLE 9 Evidence for the Role of Oxidants in Passive kinase C (PKC) (83) and mitogen-activated protein kinases
Heymann Nephritis (MAPKs) (50, 65, 137) are activated by high glucose and in-
duce renal injury. Reactive oxygen species activate PKC
There is an increased generation of hydrogen peroxide in passive Hey-
mann nephritis (152).
through redox changes in sulfhydryl groups of cysteine-rich
In a passive Heymann nephritis model of membranous nephropathy, regions of PKC (37, 39). On the other hand, PKC produces
hydroxyl radical scavengers and an iron chelator and probucol are signi- reactive oxygen species and subsequent lipid peroxidation
cantly reduced proteinuria (158, 159). (41). Hydrogen peroxide has been shown to signicantly in-
Feeding an iron-decient diet results in a reduction in proteinuria (160). crease mRNA expression and protein synthesis of TGF-1
Feeding a selenium-decient diet results in marked diminution of gluta-
thione peroxidase in anti-Fx1A-induced proteinuria (157).
(58) and bronectin (44, 58) by mesangial cells. Depletion of
cellular antioxidant capacity exaggerates TGF-1 expression
CHAPTER 92 Oxidants in Progressive Kidney Disease 2609

TABLE 10 Oxidants in Diabetic Vascular Disease


A hydroxyl radical-like species oxidizes artery wall proteins in diabetic monkey
Reactive oxygen species
o Activate aldose reductase pathway
o Induce diacylglycerol pathway
o Activate protein kinase C
o Induce advanced glycation end products
MDA in aortic smooth muscle cell is induced by hyperglycemia

Source: Pennathur S, Wagner JD, Leeuwenburgh C, Litwak KN, Heinecke JW. A hy-
droxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic
vascular disease. J Clin Invest 2001;107:853860; Nishikawa T, Edelstein D, Brownlee M.
The missing link: A single unifying mechanism for diabetic complications. Kidney Int.
2000;58(Suppl 77):S26S30; Sharpe PC, Liu W-H, Yue KKM, et al. Glucose-induced
oxidative stress in vascular contractile cells. Diabetes 1998;47:801809.

TABLE 11 Oxidants in Diabetic Nephropathy: In Vitro Studies


High glucose results in
o Reactive oxygen species generated by mesangial cells (101)
o Lipid peroxidation in isolated glomeruli which is prevented by hydroxyl radical scavengers (96)
Antioxidants prevent glucose-induced
o Activation of protein kinase C (PKC) and NK-
B (101)
o Upregulation of transforming growth factor (TGF)-1
o Upregulation of bronectin
o Upregulation of endothelin-1 (98)

Oxidants in diabetic nephropathy: in vivo studies


Glomeruli isolated from diabetic rats
o Have increased production of oxidants including superoxide and hydrogen peroxide (9798, 128)
o Have increased expression of heme-oxygenase, which is prevented by anti-oxidants (128)
o Have lipid peroxides and 8-OHdG (96)
Antioxidants prevent functional and morphological changes of diabetes (117119, 124127, 128)
Selenium-decient diet causes an increase in albuminuria, glomerular sclerosis in diabetic rats and an increase in
TGF-1 (99)
Diabetic nodular lesions in humans stain positive for malondialdehyde (95)

in glomeruli isolated from both control and diabetic rats (110) In in vivo studies, glomeruli isolated from diabetic rats
and PAI-1 expression in mesangial cells cultured under both increased production of superoxide and hydrogen peroxide
control and high glucose (46). (19, 68). The higher endothelin (ET-1) in glomeruli iso-
Antioxidants have been shown to inhibit several biologi- lated from diabetic rats is markedly attenuated by reactive
cal processes in glomeruli induced by high glucose that have oxygen species scavengers as well as the iron chelator def-
been implicated in diabetic nephropathy. Structurally differ- eroxamine (19). Kidneys from diabetic rats exhibit lipid
ent antioxidants suppress high-glucose-induced cytosolic peroxides and 8-OHdG (42). In a study published in the
reactive oxygen species generation (44) and high-glucose- Journal of Clinical Investigation, diabetic nodular lesions in
induced PKC activation in rat mesangial cells (131), proxi- humans stained positive for malondialdehyde, an index of
mal tubular cells (103), and the glomeruli of streptozotocin- lipid peroxidation (56, 85). Additional support comes
induced diabetic rats (47, 48, 84). Antioxidants also prevent from studies in which antioxidants prevent glomerular
upregulation of TGF-1 (45, 131) and bronectin (131) and renal hypertrophy, albuminuria, glomerular expression
and activation of transcription factors NF-
B and AP-1 in of TGF-1 and ECM (extra cellular matrix), and PKC
mesangial cells (44). High-glucose-induced collagen pro- activation in experimental diabetes (21, 22, 47, 48, 72, 73,
duction in rat mesangial cells was effectively prevented by 84). Reddi et al. have shown that a selenium-decient diet
two antioxidants: taurine (139) and vitamin E (138). These caused an increase in albuminuria, glomerular sclerosis,
data provide evidence that reactive oxygen species generated and plasma glucose levels in both normal and diabetic rats,
by glucose metabolism may act as integral signaling mole- and that TGF-1 is a pro-oxidant and selenium de-
cules under high glucose as in other membrane receptor ciency increases oxidative stress via this growth factor
signaling (44). (110).
2610 SECTION IV Progression of Renal Disease

In an in vivo study, Koya et al. examined the role of oxi- tial sources, including intracellular sources of iron in the
dants in a model of diabetes. There was enhanced generation kidney, is available for only acute models of renal injury.
of oxidants as measured by 2 ,7 -dichlorouorescin uores- Thus, mitochondria have been suggested as sources of iron
cence in glomeruli from diabetic rats compared with nondia- in gentamycin nephrotoxicity, whereas cytochrome C has
betic rats. Although the mRNA expression of catalase, gluta- been shown to be an important source of catalytic iron in
thione peroxidase, and Cu/Zn superoxide dismutase 2 weeks ischemic and toxic injury (7).
after the induction of diabetes was not signicantly different For iron to be important in causing renal injury, it is also
from that in control rats, mRNA and protein expression of important to demonstrate increased generation of oxidants.
heme oxygenase was markedly induced in diabetic glomeruli. The oxidants would then play a role in mobilizing iron as
Antioxidant treatment with vitamin E or probucol almost well as interacting with the mobilized iron to generate
completely normalized heme oxygenase overexpression in highly reactive metabolites. Nath and colleagues have car-
diabetic glomeruli, supporting the existence of oxidative ried out a series of studies that have provided compelling
stress in the glomeruli of early diabetes. Furthermore, anti- evidence for the role of oxidants in progressive renal disease
oxidant treatment normalized diabetes-induced renal dys- (90, 91). Increased rates of oxygen consumption, which oc-
function such as albuminuria and glomerular hypertension cur in surviving nephrons, is linked to ammoniagenesis and
and glomerular pathologies (Table 11) (70). increased generation of reactive oxygen species, both of
which have been incriminated in progressive renal injury
(91). It has been shown also that, in weanling rats, diets
ROLE OF OXIDANTS AND IRON decient in selenium and vitamin E enhance ammoniagen-
IN PROGRESSIVE KIDNEY DISEASE esis, compromise renal function in the intact kidney, and
induce tubulointerstitial injury (92).
The evidence for the role of oxidants in progressive kidney Several studies have examined the effect of an iron-
disease has been reviewed and consists of the demonstration decient diet or iron chelators on progression of chronic
of enhanced production of oxidants, evidence that oxidants kidney disease. Alfrey et al. have shown a marked effect of
induce similar morphological and functional changes as seen an iron-decient diet or an iron chelator on preventing the
in progressive kidney disease, and the benecial effects of development of tubulointerstitial disease and renal func-
antioxidants (Table 12) (53). The role of inammatory cells tional deterioration in nephrotoxic serum nephritis (2, 3).
in progressive kidney disease has also been reviewed (97). Remuzzi et al. have shown that rats fed an iron-decient
This section of the chapter emphasizes the role of iron be- diet had signicant reduction in proteinuria and developed
cause of the possibility of using iron chelators in preventing less glomerulosclerosis (114). An iron chelator signicantly
progression. The data supporting the role of iron in models reduced iron accumulation and tubular damage in rat rem-
of progressive renal disease consist of demonstration of in- nant kidneys (a model for progressive renal disease) (89).
creased iron in the kidney in these models of progressive The precise cellular mechanisms by which oxidants and
kidney disease; enhanced oxidant generation, which pro- iron participate in progression are not known. However,
vides a mechanism by which iron can be mobilized; and, oxidants and iron have many cellular effects that are poten-
more directly, the benecial effect of iron-decient diets and tially important in tubulointerstitial damage, brosis, and
iron chelators (Table 12). Rats with proteinuria have in- matrix accumulation. For example, it is well established that
creased iron content in proximal tubular cells, and iron ac- oxidants and iron play an important role in cellular injury
cumulation was the only independent predictor of both and cell death, including apoptosis. Thus conceivably they
functional and structural damage (51). Similarly, it has been could play a role in tubular atrophy and loss of cells, which
shown that there is a substantial iron accumulation associ- is a common feature of progressive renal disease. In addition,
ated with increased cortical malondialdehyde in proximal lipid peroxidation has been shown to be important in induc-
tubular cells in the remnant kidney, suggesting reactive oxy- tion of collagen gene expression (57) and may thus contrib-
gen species generation. Iron accumulation has also been ute to renal brosis.
studied in human chronic renal disease (88).
The sources of increased iron in the kidney have not
been well-delineated, but Alfrey et al. have suggested that CONCLUSIONS
urinary transferrin provides a potential source of iron. Glo-
merular injury of any type impairs glomerular permselec- A sufcient body of in vitro and in vivo information exists
tivity, thereby leading to the leakage of proteins, including to postulate that oxidants appear to be important media-
transferrin, into the urinary space. At a pH below 6.5, iron tors in glomerular pathophysiology and in progressive
has been shown to be dissociated from transferrin in urine. kidney disease. Nonetheless the multifaceted nature of tis-
As pH decreases as urine courses along the nephron, iron sue injury makes it almost a certainty that the cooperative
is released from transferrin (2, 20), thus providing a source and sometimes complex interactions between different in-
of iron that could act on renal tubular epithelial cells or be jurious mechanisms are important in the nal expression of
absorbed into the tubules. Information about other poten- injury.
CHAPTER 92 Oxidants in Progressive Kidney Disease 2611

TABLE 12 Oxidants and Iron in Progressive Kidney Disease


Oxidative Stress in Progression of Kidney Injury (53)
Generation of reactive oxygen species
Oxidative stress induces similar functional and morphological changes
Antioxidants protect against progression

Role of Iron in Progressive Renal Disease


An increased amount of iron has been shown in the kidneys of
animals (51,94)
and humans (88) with kidney disease

Progression of renal failure in nephrotoxic nephritis model is prevented by an


iron-decient diet (2)
iron chelator (3)

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