Endogenous Inhibitors of Kidney Inflammation
Jessica Trostel,
Gabriela E. Garcia
Jessica
Trostel, Gabriela E. Garcia, Department
of Medicine, Division of Renal Diseases and Hypertension, Aurora, CO 80045, the
United States
Correspondence to:
Gabriela E. Garcia, Department of Medicine, Division of Renal Diseases and Hypertension,
University of Colorado Denver, 12700 East 19th Avenue, Room 7103, Aurora, CO
80045, the United States
Email:
Gabriela.garcia@ucdenver.edu
Telephone: +1-303-724-4897
Fax: +1-303-724-4868
Received: June 4, 2015
Revised: July 12, 2015
Accepted: July 16, 2015
Published online: October 26, 2015
ABSTRACT
Although inflammation is the physiological response to
pathogen invasion and tissue damage, it can also be responsible for significant
tissue damage. Therefore, the inflammatory response must be carefully regulated
to prevent critical inflammatory damage to vital organs. Typically, local
endogenous regulatory mechanisms adjust the magnitude of the response such that
the injurious condition is resolved and homeostasis is mantained. Humoral
mechanisms that restrain or inhibit inflammation include glucocorticoid
hormones, anti-inflammatory cytokines such as IL-10 and transforming growth
factor-¦Â (TGF-¦Â), and soluble cytokine receptors; other mediators facilitate
tissue healing, like lipoxins and resolvins. There is growing evidence that
inflammation plays a critical role in the development and progression of heart
disease, cancer, stroke, diabetes, kidney diseases, sepsis, and several
fibroproliferative disorders. Consequently, understanding the mechanisms that
regulate inflammation may offer therapeutic targets for inhibiting the
progression of several diseases. In this article, we review the significance of
several novel endogenous anti-inflammatory mediators in the protection from
kidney injury and the potential of these regulatory molecules as therapeutic targets
for treatment of kidney inflammatory diseases.
© 2015 ACT. All rights reserved.
Key words: Inflammation;
fibrosis; adenosine; inflammatory reflex; Slit
Trostel J, Garcia GE. Endogenous Inhibitors of Kidney
Inflammation. Journal of Nephrology Research 2015; 1(2): 61-68 Available from: URL:
http://www.ghrnet.org/index.php/jnr/article/view/1237
INTRODUCTION
Inflammation is an essential immune respose that enables survival
during infection or injury and mantains tissue homeostais under several
conditions. The inflammatory response consists of four components: Inflammatory
inducers, the sensors that detect the inducers, the inflammatory mediators
induced by the sensors, and the target tissues[1]. In many cases,
inflammation is self-limiting because of intrinsic mechanisms designed to
control the inflammatory process. Resolution of inflammation is an active and
highly regulated process that involves cells and soluble factors.
Cells
contributing to resolution of inflammation
During inflammation, apoptotic cells are ingested typically by
macrophages; and ingestion of apoptotic cells triggers macrophages to release
anti-inflammatory cytokines such as TGF-¦Â and IL-10. Apoptosis is not the only
mechanism by which macrophages switch from being pro-infammatory at the outset
of an inflammatory response to anti-inflammatory later in the process. Tissue
damage induced by inflammation promotes production of glucocorticoid hormones
that can convert monocytes/macrophages from pro-inflammatory to an
anti-inflammatory state.
Other cells
that contribute to resolution of inflammation are T regulatory cells. These T
cells which are characterized by the secretion of TGF-¦Â and IL-10, also can
suppress inflammation. T regulatory cells have been found to suppress various
immune cells such as CD8+ T cells, dendritic cells (DCs),
monocytes/macrophages, B cells, natural killer cells, and natural killer T
cells. T regulatory cells are essential to maintain a non-inflammatory
environment in the gut, to suppress allergic immune responses to environmental
food antigens, and to decrease chronic inflammation[2,3].
Soluble factors
contributing to resolution of inflammation
Soluble products that contribute to resolution of inflammation include
the inflammation-resolving cytokines IL-10 and TGF-¦Â. Other secreted proteins
driving resolution include secretory leukocyte protease inhibitor (SLPI) that
supresses the abiliy of TNF-¦Á to activate neutrophils.
Other secreted
proteins besides cytokines play controlling roles in the resolution of
inflammation including adenosine and acetylcholine. Adenosine signaling through
the A2A adenosine receptor (A2AR) on immune cells is essential to supress
inflammatio. In A2AR deficient mice the intensity and duration of inflammatory
responses are increased.
Acetylcholine
release after vagus nerve stimulation inhibits production of TNF-¦Á, IL-1¦Â,
IL-6, and IL-18 by macrophages via activation of the ¦Á7 nicotinic acetylcholine
receptor (¦Á7nAChR).
In sum,
multiple mechanisms normally ensure resolution of inflammation. However,
nonresolving inflammation can be caused if the inflammatory trigger is not
eliminated, it is prolonged, or it is excessive[1,3].
In the kidney,
the concept of ‟glomerular self-defense¡± was
introduce by Kitamura and Fine in 1999. They clearly demonstrated that during
inflammatory injury, glomerulus acquires the potential for protecting itself
form further damage[4]. The authors identified intracellular
signaling molecules that impose checks and balances on pro-inflammatory
pathways during kidney inflammation, such as heat shock proteins, antioxidant
enzymes, kinase-inhibiting proteins, and cyclin kinase inhbitor. In addition,
the role of secreted/extracellular formation of soluble products driving
resolution of inflammation was described, including: inhibitors of cytokines
and growth factors, proteinase inhibitors, complement regulatory proteins,
oxygen raical scavengers, and inhbitors of adenine nucleotides[4].
Evidence
supports that inflammation has an importat role in the development and
progression of most chronic kidney diseases. It involves a complex inflammatory
process in which following tissue injury, epithelial/endothelial cells release
cytokines/chemokines to recruit and activate inflammatory cells. Activated
inflammatory cells secrete profibrotic cytokines and cytokines/chemokines to
attract more inflammatory cells and amplify the inflammatory reaction.
Mesangial cells and fibroblasts are activated, tubular epithelial to
mesenchymal is trigged, and excessive extracellular matrix deposition is
observed (Figure 1)[5,6]. Therefore, advances in our understanding
of kidney inflammation would be of great therapeutic benefit for inhibiting
progressive kidney fibrosis.
In this review
we highlight novel endogenous mechanisms underlying resolution of kidney
inflammation and discuss how these mechanisms can be targeted to protect from
kidney injury in inflammatory diseases.
Adenosine and its
receptors
Adenosine is an endogenous purine nucleoside present
in the extracellular space at low concentrations; however, elevation in
extracellular adenosine is found in conditions of ischemia, hypoxia,
inflammation, and trauma[7,8]. Adenosine following its release binds
specific cell-surface adenosine receptors. There are four distinct receptor
subtypes for adenosine, that is A1, A2A, A2B
and A3 adenosine receptors. Adenosine receptors are G-protein
coupled receptors and particularly Gs-protien-coupled A2A and A2B
adenosine receptors can increase intracellular cAMP levels by activating
adenylate cyclase. Adenosine A2A receptors (A2ARs) are
generally regarded as the receptor subtype most relevant for the
anti-inflammatory effect of adenosine. Activation of A2AR on macrophages
can inhibit the production of interleukin (IL) -12, TNF-¦Á, and NO, and enhance
the secretion of IL-10 in response to lipopolysaccharide[9].
Critical role of A2AR in the control of
inflammation
A2ARs are found ubiquitously in the body; their expression
is highest in the immune system and the stratiopallidal sysem in the brain.
Adenosine triggers A2AR on acivated immune cells and leads to an
increase in intracellular cAMP. cAMP, an intracellular off signal, inhibits
intracellular signal pathways, leading to the interruption of proinflammatory
processes in immune cells. The esencial role of A2ARs in downregulation
of inflammation and protection from tissue injury was demonstated by markedly
enhanced liver damage and sepsis in A2AR-deficient mice using
sub-therhold doses of inflammatory stimuli[10].
Kidney
protection from ischemia-reperfusion by A2ARs
Pharmacological actication of A2ARs attenuates
ischemia-reperfusion injury in mice and rats. Pretreatment with a selective
agonist of A2ARs (5 hours before ischemia) improves kidney function,
reduces tubular injury, and ischemic necrosis. Importantly, delayed
administration of the A2AR agonist until the reperfusion period is
able to reduce plasma creatinine levels and kidney injury[11-13].
This protection is mediated by reduction in the expression of adhesion
molecules (ICAM-1 and P-selectin) in endothelial layers of peritubular
capillaries and interlobular arteries[12]. Tissue protection of A2AR
agonists in ischemia-reperfusion requiere activation of receptors expressed on
bone marrow-derived cells. Using chimeric mice in which bone marrow was ablated
by lethal radiation and reconstituted with donor bone marrow cells derived from
WT or A2AR-KO mice, it was observed that A2AR activation
reduced the induction of pro-inflammatory cytokines in WT mice receiving WT
bone-marrow cells (WT ¡ú WT mice) but not in WT mice receiving bone-marow cells
lacking the A2AR gene (A2AR KO ¡ú WT mice)[14].
The signaling intermediate of A2AR-mediated kidney protection is
cAMP, since in vivo treatment with cAMP mimics the effect of A2AR
agonists and in vitro studies, A2AR agonists increase cAMP
accumulation and decrease activated neutrophils adherence[11,15].
Role of A2AR
activation in diabetic nephropathy
Activation of A2AR before or after the induction of diabetes
protects kidneys from injury. Macrophages infiltration and the levels of
cytokines in the urine (CCL2/MCP-1, TNF-¦Á, and IFN-) were significantly reduced in rats treatd with a A2AR-agonist
(ATL-146e, delivered through osmotic minipup). As a consequence of the
reduction of kidney inflammation the renal function was better preserved in
rats treated with ATL-146e. In addition, interstitial fibrosis, mesangium
expansion, and thickness of the tubular basement membrane were signifcantly
attenuated in the ATL 146e-treated groups[16]. Interestingly,
pharmacological activation of A2AR before or after induction of
diabetes restored the mRNA expression of podocin and nephrin[16].
Activation of
podocytes A2AR preserves its function and structure
Although A2ARs are found predominatly in immune cells, it
was demonstrated that inmortalized mouse podocytes express A2ARs.
Activation of A2ARs in puromycin aminonucleoside nephropathy, a
model characterized by proteinuria and effacement of podocytes foot processes,
attenuated these effects[17].
A2ARs
activation protects form kidney injury in the acute and progressive phases of
glomerulonephritis
Crescentic glomerulonephritis (GN) is a life-threating disease in which
glomerular inflammation progresses rapidly into chronic kidney disease. Using a
model of anti-glomerular basement membrane (GBM) antibody-associated
glomerulonephritis (GN), that is analogous to human crescentic GN, we found
that macrophages infiltrating nephritic kidney express A2AR[18].
Pharmacological activation of A2ARs in the acute phase of the
disease (8 hours after the induction of the disease) or in the progressive
phase of the disease (at day 6 after the injection of the antibody) was able to
protect from the acute and established injury by decreasing macrophages and CD8+
cells infiltration and suppressing the expression of chemokines[18,19].
Notably, when pharmacological activation of A2AR was delayed until
extracellular matrix deposition was established (day 14 after the induction of
the disease), glomerular macrophages infiltration was reduced by 83%. There was
also a marked improvement in glomerular lesion histology, as well as decreased
proteinuria. A2AR activation significantly reduced type I, III, and
IV collagen deposition, and E-cadherin expression was restored in association
with a reduction of ¦Á-smooth muscle actin-positive myofibroblasts in the
interstitium, suggesting that activation of A2ARs arrest kidney
disease progression[19].
A2AR
attenuates kidney interstitial fibrosis in unilateral ureteral obstruction
model (UUO)
Using the unilateral ureteral obstruction model it
was demonstrated that pharmacological activation of A2AR starting at
day one after UUO, significantly decreased collagen deposition at day 3 after
UUO. At day 7 after induction of UUO, collagen deposition, alpha-smooth muscle
actin expression and TGF-¦Â expression were reduced and E-cadherin expression
was restored. In contrast, in A2AR deficient mice, kidney
interstitial fibrosis was exacerbated[20]. The protective effect of
A2AR activation, however, was lost at day 14 post-UUO. These studies
suggest that pharmacological activation of A2AR protects from early
progressive interstitial fibrosis in UOO.
A2B
adenosine receptors
Stimulation of A2BR upregulates IL-6 and plays a
pro-inflammatory role in the exacerbation of allergic asthma and colitis.
However, studies using gene-deficient mice have shown an anti-inflammatory role
of A2B, since A2BR deficient mice have spontaneous
vascular inflammation and exacerbated lung injury. Because A2BR are
expressed on both immune (macrophages, lymphocytes, dendritic cells, and
neutrophils) and non-immune cells (smooth muscle cells, endothelial cells, and
epithelial cells), these controversial results may be caused by difference in
cell type specific responses to adenosine via A2BR during inflammation[8,21-23].
A2BR
protects kidney from ischemia during ischemia preconditioning (IP)
IP protects from kidney injury and this effect was
associated with increased expression of A2BR within the
reno-vasculature. Moreover, mice lacking this receptor were not protected from
ischemia and the anti-inflammatory effects of kidney IP were abolished[24].
Using A2BR bone marrow chimeric mice it was demonstrated that A2BR-/-
¡ú A2BR+/+ chimeric mice showed similar degree of kidney protection
by IP as A2BR+/+, suggesting that reno-vascular A2BR (but
not bone-marrow cells A2BR) is responsible for increased kidney
resistance to ischemia and attenuates ischemia reperfusion injury[24].
A2BR
attenuates diabetic nephropathy
In a model of diabetic nephropathy the expression of A2BR
was induced in the kidney vasculature. Treatment with an A2BR
agonist attenuated histological changes in the kidney, reduced albuminuria,
VEGF expression, and urinary MCP-1 excretion, and restored the expression of
nephrin. In contrast, in A2BR deficient mice diabetic nephropathy
was more severe, indicating that A2BR could be a therapeutic target
for diabetic nephropathy[25].
A2BR-mediated
induction of IL-6 contributes to kidney fibrosis
Recently, it was reported the development of kidney fibrosis in ADA
deficient mice (that have increased levels of adenosine because the catabolism
of adenosine is prevented due to the lack of adenosine deaminase) and in
angiotensin II-infused mice. Treatment with an A2BR antagonist or
genetic deletion of A2BR attenuated fibrotic changes, suggesting
that adenosine/A2BR signaling was responsible for kidney fibrosis.
The authors also found that unilateral ureteral obstruction-induced fibrosis
was attenuated in A2BR deficient mice. Interestingly, using kidney
explants was demonstrated that adenosine increased IL-6 and pro-collagen mRNA
levels, effects that were abolished using explants from A2BR deficient
mice or an A2BR antagonist[26]. These studies suggest
that adenosine/A2BR signaling induces IL-6 production to contribute
to kidney fibrosis.
Inflammatory
reflex/Cholinergic anti-inflammatory pathway
There is increasing evidence for a bidirectional communication between
the immune and neuroendocrine systems. Cytokines, peptide hormones, and
neurotransmitters, as well as their receptors, are present in the brain and in
the endocrine and immune systems. Several immunoregulatory cytokines, including
IL-1, IL-2, IL-6, IFN-, and TNF are produced not only in the immune system
but in the neuroendocrine system as well. On the other hand, the synthesizing
enzyme choline acetyltransferase, the signaling molecule acetylcholine, and the
respective receptors (nicotinic and muscarinic) are expressed in non-neuronal
cells. As an example, acetylcholine, the principle vagal neurotransmitter, is
produced by epithelial cells, T lymphocytes, and endothelial cells. Recently,
it has been identified that stimulation of the vagus nerve activates adrenergic
splenic neurons to release norepinephrine that stimulates acetylcholine
synthesis in splenic memory T cells. Acetylcholine released by these splenic T
cells binds to a7 nicotinic acetylcholine receptor (a7nAChR) expressed on macrophages in the red pulp and marginal zone to
suppress the synthesis and release of cytokines[27-29]. Vagal nerve
stimulation (VNS) protects against systemic inflammation in experimental
ischemia and reperfusion, hemorrhage and resuscitation, pancreatitis, colitis,
endotoxemia, septic shock, and severe sepsis[27,30]. In addition,
stimulation of the a7nAchR attenuates experimental arthritis and
pancreatitis[31,32]. In contrast, in ¦Á7nAchR-deficient mice,
inflammation is markedly increased in endotoxemia and adjuvant arthritis[29,33].
Inflammatory
reflex attenuates kidney ischemia-reperfusion injury
Pre-ischemic treatment with cholinergic agonists, nicotine or GTS-21 (a
selective ¦Á7nAChR agonist), reduced neutrophil infiltration and TNF production,
and as a consequence of the decreased kidney inflammation, the acute tubular
damage and kidney dysfunction were attenuated. Interestingly, in vagotomized
animals, pretreatment with nicotine significantly attenuated kidney injury
after ischemia-reperfusion, suggesting that activation of ¦Á7nAChR localized in
the kidney mediates the protective effect of the cholinergic agonists[34].
Unfortunately, delayed treatment with ¦Á7nAChR agonists after the onset of
reperfusion, did not protect kidneys from injury.
More recently
it was demonstrated that in mice exposed to ultrasound (US) 24 hours before
ischemia-reperfusion, the renal function was preserved and the kidney injury
was attenuated by activating the cholinergic anti-inflammatory pathway.
Splenectomy, lack of CD4+T cells, and absence of ¦Á7nAChR removed the
protection elicited by US, supporting the key role of the inflammatory reflex
in US-prevention of ischemia-reperfusion injury[35].
Although these
studies suggest that vagus nerve, spleen, T, cells and the ¦Á7nAChR are required
for kidney protection in ischemia-reperfusion, the possibility that localized
renal ¦Á7nAChR protects from kidney damage during ischemia-reperfusion cannot be
excluded[34,36].
Interestingly,
in a recent study, adoptive transfer of splenocytes from mice previously
exposed to ultrasound protected recipient mice from kidney ischemia-reperfusion
injury, suggesting that ultrasound alone affects splenocyte function[36].
Nicotinic
acetylcholine receptor agonists protects septic acute kidney injury
In a model of acute kidney injury induced by lipopolysaccharide (LPS)
in mice, administration of nicotine or GTS-21 (a selective ¦Á7nAChR agonist),
previous to lipopolysaccharide administration, reduced kidney damage, leukocyte
infiltration, serum TNF-¦Á, and kidney concentration of cytokines/chemokines. In
addition, ¦Á7nAChR agonists attenuated kidney NF¦ÊB activation, an effect that
was associated with decreased proteasome activity in renal tissue in vivo.
These studies indicate that nicotinic agonists attenuates LPS-induced kidney
injury by suppression of inflammation and proteasome activity[37].
Consequences of
impairment of cholinergic anti-inflammatory pathway
It has been reported that in the coarctation-induced hypertension model
in rats and in spontaneously hypertensive rats (SHRs), the vagal tone, the
expression of the vesicular acetylcholine transporter (VAChT) (that takes
acetylcholine into secretory organelles where the transmitter is stored until
release), and the ¦Á7nAChR were significantly reduced. In addition,
proinflammatory cytokines were increased in the kidney, heart and aorta in
SHRs. Evidence of hypertension induced-end-organ damage was also found in SHRs.
These effects were prevented when SHRs were treated chronically with
PNU-282987, an ¦Á7nAChR agonist. Importantly, in ¦Á7nAChR deficient mice
subjected to hypertension by clipping 1 kidney artery, the levels of
proinflammatory cytokines and hypertension induced-end-organ damage were
greater than in WT controls[38]. These studies suggest that
diminished ¦Á7nAChR signaling is a major mechanism in the pathogenesis of
cardiovascular inflammation and end organ damage in hypertension.
Recently, we
found that the absence of ¦Á7nAChR in glomerulonephritis amplifies inflammation
and accelerates onset of fibrosis, indicating that the endogenous nicotinic
acetylcholine receptor ¦Á7 subunit is essential to inhibit inflammation and
progressive kidney injury in glomerulonephritis[39].
Slit proteins
Slit are secret proteins known for their role of
repulsion in axon guidance and neuronal migration[40]. Slit proteins and their Robo receptors have
been also shown to play a crucial role in development of non-CNS organ systems
including the kidney, heart, and lung. Both neuronal and leukocyte cell
migration share similar characteristics and, interestingly, Slit has been found
to inhibit leukocyte migration[41].
There are
three Slit genes and each gene has a distinct expression pattern: Slit 1 is
specific to the brain, Slit 2 and Slit 3 are expressed in the brain as well as
other tissues. The expression of Slit 2 in the kidney and lung is comparable to
that in the brain. Expression of Slit3 is the highest in the lung and also
detectable in the kidney, brain, heart, spleen, and lymph nodes[41].
Slits modulate
inflammation in experimental crescentic glomerulonephritis
In glomerulonephritis, endogenous glomerular Slit2 expression was
downregulated. Treatment with recombinant Slit2 in the acute phase of the
disease (treatment commenced 6 hours after the induction of the disease)
resulted in improved kidney function, less kidney damage, and reduced
macrophage infiltration. These studies suggest that Slit2, given early, is able
to inhibit leukocyte recruitment during the initiation period and thus
attenuate the disease process. However, treatment delayed on day 7 after the induction
of the disease did not improve kidney function although kidney damage was to
some extent improved. These results indicate that late treatment with
recombinant Slit2 was unable to resolve inflammation that was already present
but may have been able to inhibit further leukocyte recruitment[42].
Slit 2
attenuates kidney ischemia-reperfusion injury and dysfunction
Slit2 protein is detected in the glomeruli and tubulointerstitium of
normal kidneys. However, endogenous levels of Slit2 were significant downregulated
after ischemia-reperfusion. Administration of exogenous Slit2 1 hour before the
induction of the ischemia-reperfusion injury, prevented acute tubular injury
and markedly reduced infiltration of neutrophils and monocytes/macrophages into
the post-ischemic kidney[43,44]. In in vitro studies, it was
found that Slit2 reduced neutrophil capture, neutrophil adhesion to activated
endothelial cells, and chemoattractant-induced neutrophil transendothelial
migration[44]. These studies indicate that Slit2 potently inhibits
multiple steps involved in recruitment of circulating neutrophils and that
Slit2 represents a potential strategy for the prevention and treatment of acute
kidney injury.
Stanniocalcin
Stanniocalcin is a naturally occurring and ubiquitously expressed
calcium-regulating peptide. The mammalian stanniocalcin-1 (STC-1) gene is
widely expressed and its mRNA levels are highest in the ovary, followed by
kidney, adrenal, prostate, and heart. Within the kidneys, STC-1 is involved in
transport-related processes, organogenesis, and mitochondrial function[45].
From an inflammatory perspective, STC-1 attenutes chemokinesis and decreases
the chemotactic response to chemokines by blunting the rise in intracellular
calcium, following chemokine stimulation in macrophages. In addition, STC-1
suppresses superoxide generation in macrophages[46,47].
Stanniocalcin
attenuates inflammation and kidney injury in anti-glomerular basement membrane
(GBM) glomerulonephritis (GN)
In WT mice, anti-GBM GN led to a glomerular accumulation of
macrophages, crescent formation, sclerotic glomeruli, and tubulinterstitial
injury. Macrophage infiltration was significantly attenuated in STC-1
transgenic (Tg) mice and consequently, the crescentic formation, sclerotic
glomeruli, and tubulointerstitial injury were markedly reduced. In addition,
kidney function was preserved in STC-1 Tg mice. Interestingly, infiltration of
T cells in the interstitium were similar in WT and STC-1 Tg mice, suggesting
that STC-1 has no significant effect on T-cell infiltration. In addition, there
was no difference in the expression of cytokines characteristic of TH1- or
TH2-mediated T-cell responses, suggesting that STC-1 does not affect T-cell
activation[48].
Stanniocalcin
protect from ischemia-reperfusion injury
Using mouse ischemia-reperfusion kidney injury model in wild-type (WT)
and STC-1 transgene (Tg) mice, that display in the kidney preferential
expression of STC-1 Tg in endothelial cells and macrophages, it was observed
that transgenic overexpression of STC-1 confers resistance to
ischemia-reperfusion. In WT mice kidney function was decreased and cellular
vacuolization, tubular dilatation, and cast formation were observed following
ischemia-reperfusion. Kidney injury was associated with increased macrophages
and T cells infiltration. In contrast, in STC-1 Tg mice the kidney function was
preserved and kidney injury prevented. Protection form kidney injury in STC-1
Tg mice was mediated through suppression of oxidant stress. In WT kidneys
marked elevation in superoxide and hydrogen peroxide was observed but not in
STC-1 Tg kidneys. However, pre-treatment of STC-1 Tg mice with paraquat (a
generator of reactive oxygen species) at a low dose, which does not produce
kidney injury, reproduced the results observed in WT mice after
ischemia-reperfusion.
The protective
role of stanniocalcin in ischemia-reperfusion was further supported by the
finding that stanniocalcin deficient mice displayed high susceptibility to
ischemia-reperfusion damage[49,50].
Perspective
One of the most challenging aspects of studying inflammation is the
diversity and complexity of the inflammatory mediators and their effects on
target tissues, making the development of anti-inflammatory therapy singularly
difficult.
Anti-inflammatory
agents should be active drugs that reduce production or activities of
proinflammatory mediators. In addition, therapies need to have minimal risks of
organ toxicity while ensuring that host immune defense is not impaired.
Therapeutic strategies should involve combined interventions and each
intervention should target at least one pahway, not just a molecule.
Although new
agents are in rapid stage of development, the reinforcement of endogenous
defense mechanims by pharmacological manipulations (for example, using
agonists) may provide novel avenues to the treatment of inflammatory diseases.
Notably, targeting natural regulators of inflammation should be associated with
less secondary effects.
Endogenous mechanisms of downregulation of inflammation
could be used as follow: A2AR agonists, A2BR agonists, Slit2, VNS/¦Á7nAChR
agonists, and stanniocalcin could be used to prevent ischemia-reperfusion
injury. In the early phase of kidney diseases A2AR could inhibit the
production of pro-inflammatory mediators from inflammatory cells, induce the
production of the anti-inflammatory IL-10, and protect podocytes. Slit2 and
stanniocalcin may prevent infiltration of inflammatory cells and avert
amplification of the inflammation; activation of ¦Á7nAChR may inhibit the
production of pro-inflammatory mediators by macrophages and avoid activation of
inflammatory cells. Treatment with A2AR agonists once the disease is
established may arrest the progression of kidney diseases. In table 1 we
summarize the potential therapeutic applications of natural inhibitors of
inflammation in kidney diseases, and include the table.
AKNOWLEDGMENT
This work was supported in part by Norman S. Coplon Grant (G.E.G.) and
National Institutes of Health DK082509 (G.E.G.).
This
manuscript is a tribute to and in memory of Lili Feng, a model scientist that
always demonstrated equal creativity and talent as an investigator. Lili Feng
was recognized as a superb mentor to young scientists, many of whom have gone
on to distinguished careers in the biomedical sciences.
CONFLICT OF INTERESTS
The authors declare no conflict
of interest.
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Peer reviewer: Monchai Siribamrungwong, Renal
Unit, Department of Medicine, Lerdsin General Hospital, College of Medicine,
Rangsit University, 190 Silom Road, Bangrak, Bangkok, 10600, Thailand.
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