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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