reaping the benefits of renal protective lipid autacoids

MECHANISMS

DRUG DISCOVERY

TODAY

DISEASE

Drug Discovery Today: Disease Mechanisms Vol. 4, No. 1 2007

Editors-in-Chief

Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA

Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA

Renal diseases

Reaping the benefits of renal protectivelipid autacoidsKarsten Gronert*, Iram R. HassanNew York Medical College, Department of Pharmacology, Basic Science Building, Valhalla, NY 10595, USA

A key feature in the pathophysiology of acute renal

injury and glomerulonephritis is exacerbated or non-

resolving inflammation. A rapidly evolving field has

identified lipoxins and novel v-3 lipid autacoids as

important mediators of inflammatory resolution.

These renal lipid autacoid circuits counterbalance

proinflammatory cascades, are antifibrotic and main-

tain renal function. Therapeutic or genetic amplifica-

tion of protective lipid autacoid circuits heralds a new

strategy to halt progressive renal disease and acute

renal injury.

*Corresponding author: K. Gronert ([email protected])

1740-6765/$ � 2007 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddmec.2007.06.002

Section Editor:Michael S. Goligorsky – Renal Research Institute, New YorkMedical College, Valhalla, NY, USA

Introduction

Inflammation is an essential response to tissue injury,

hypoxia, toxins and infection [1–3]. Hence, inflammation

is a prominent feature in the pathology of many renal dis-

eases, especially glomerulonephritis and acute kidney injury

[2,4–6]. Inflammation is initiated and propagated by a net-

work of proinflammatory mediators, and execution of the

acute response must include counter-regulatory signals,

which control leukocyte activation and promote resolution

to restore homeostasis [1,3]. Dysregulation of inflammation

as a consequence of aberrant amplification of proinflamma-

tory circuits and insufficient counterregulatory signals leads

to failed inflammatory resolution, which paves the way for

progressive renal injury. Despite major advances, mortality

due to acute kidney injury remains high. A rapidly evolving

field, focused on defining proresolution and counterregula-

tory pathways, has identified essential novel lipid autacoids

[1,3,7] that promote resolution of inflammation and protect

against ischemic renal injury. Amplification of these protec-

tive circuits provides a fresh approach to managing kidney

injury.

Protective eicosanoid circuits in the kidney

Eicosanoids are derived from the essential fatty acid, arachi-

donic acid (AA, v-6 C20:4). Two families of enzymes, cycloox-

ygenases and lipoxygenases, metabolize AA to form lipid

autacoids, each with specific hydroxyl group stereochemistry

and double bond geometry. It is well appreciated that the

cyclooxygenase-derived prostaglandins and thromboxane

and the lipoxygenase-derived leukotrienes and lipoxins play

important roles as regulators of inflammatory and immune

functions [1–3,7–9]. These locally produced and short-lived

lipid signals mediate their potent bioactions via distinct

classes of G-protein coupled receptors. The large family of

cytochrome P450 (CYP450) enzymes, which includes AA in

their impressive repertoire of potential substrates, also gen-

erates potent epoxide- and hydroxyeicosanoids, which repre-

sent the third enzymatic pathway for formation of bioactive

eicosanoids [8]. Together with prostaglandins, CYP450-

derived eicosanoids play a crucial role in the control of renal

blood flow and glomerular filtration, which underscores the

importance of eicosanoid biosynthetic pathways in the nor-

mal physiology of the kidney. Indeed, the inducible prosta-

glandin H synthase (COX-2), which was linked to

inflammatory diseases and became a major pharmaceutical

3

mailto:[email protected]

http://dx.doi.org/10.1016/j.ddmec.2007.06.002

Drug Discovery Today: Disease Mechanisms | Renal diseases Vol. 4, No. 1 2007

target for the development of selective inhibitors, was first

shown to be constitutively expressed in the kidney [8]. The

adverse renal effects and increased incidence of myocardial

infarction and thrombotic stroke in patients treated with

COX-2 selective inhibitors emphasizes the high risk of global

inhibition of a pathway that is presumed to be proinflamma-

tory.

A rapidly evolving field of research provides strong evi-

dence for a novel paradigm, namely, that acute inflammation

is a highly regulated and beneficial process whose successful

outcome depends on balanced formation of pro- and anti-

inflammatory lipid autacoids and the active resolution of

leukocytes [1,3]. An inherent problem is the fact that lipox-

ygenase, cyclooxygenase and CYP450 each can generate or

initiate formation of both pro- and anti-inflammatory eico-

sanoids. Hence, pharmacological inhibition of biosynthetic

enzymes disrupts the delicate balance of inflammatory med-

iators and can lead to a dysregulated acute inflammatory

response. The 1984 discovery of a new class of eicosanoids,

lipoxins, championed the concept of anti-inflammatory and

proresolving lipid autacoids [10] and has led to the discovery

of other anti-inflammatory eicosanoids such as the cyclopen-

tenone prostaglandin, 15-deoxy-PGJ2 [1]. A wealth of data

provides a compelling rationale to develop a new therapeutic

strategy, namely, to control inflammation by amplifying

endogenous pathways of proresolution. In addition to lipid

autacoids, there are other important endogenous chemical

mediators that have anti-inflammatory action and are poten-

tial therapeutic targets, such as adenosine, corticosteroids

and carbon monoxide, to name a few. However, unlike the

lipid autacoids discussed below, these chemical mediators

have pleiotropic effects, and it is unclear if their bioactions

extend beyond suppressing inflammatory and immune

responses.

Table 1. LXA4, DHA and DHA-derived lipid mediator use in an

Renal disease Model Treatment

Acute renal failure Murine ischemia-reperfusion injury LXA4 analog

Murine ischemia-reperfusion injury LXA4 analog

Murine ischemia-reperfusion injury DHA

Murine ischemia-reperfusion injury DHA, Protec

Murine ischemia-reperfusion injury Protectin D1

Resolvin D1

Glomerulonephritis Concanavalin A-ferritin-induced

glomerulonephritis

LXA4

Nephrotoxic serum nephritis in

P-selectin knockout

LXA4

Antiglomerular basement membrane

glomerulonephritis

Transfection

with 15-LOX

Mycotoxin deoxynivalenol-induced

IgA nephropathy

DHA

Vascular tone Mesangial cell contraction LXA4

4 www.drugdiscoverytoday.com

Lipoxins: A prominent anti-inflammatory and

proresolving eicosanoid circuit

An impressive body of work has established that the eicosa-

noid, lipoxin A4 (LXA4), is an important mediator for the

resolution of acute inflammation [1,3,7,9–13]. Lipoxins are

lipoxygenase-interaction products that are formed from the

essential fatty acid AA, during neutrophil (PMN) interactions

with endothelial cells, epithelial cells or platelets. Experimen-

tal animal models have demonstrated LXA4 biosynthesis

peaks during the resolution phase of acute inflammation.

Endogenous formation of LXA4 has been clearly demon-

strated in humans and animal models of inflammatory

diseases including experimental immune complex glomer-

ulonephritis and acute ischemic renal injury. Moreover,

transgenic mice that express the human lipoxin A4 receptor

(ALX) have provided strong direct evidence that this

lipid circuit has protective roles in acute inflammation

and innate host defense and promotes inflammatory resolu-

tion [1,10,13].

Humans and rodents generate an endogenous isomer of

LXA4, 15-epi-LXA4, which is formed via the intermediate

15R-hydroperoxy-HETE, a product of aspirin-acetylated

COX-2 and CYP450. 15R-H(p)ETE is an epimer of the lipox-

ygenase-derived 15S-H(p)ETE, and the switch in chirality in

15-epi-LXA4 decreases the rate of metabolic inactivation,

which has led to the development of metabolically stable

15-epi-LXA4 mimetics. These mimetics have enabled detailed

structure–function studies and provided essential tools to

establish the endogenous role of the LXA4 circuits in inflam-

matory diseases and the therapeutic potential of amplifying

this anti-inflammatory pathway. Studies on animal models of

renal disease have directly demonstrated the efficacy (Table 1)

of treatment with LXA4 or LXA4 mimetics in limiting the

sequelae of ischemic renal injury and glomerulonephritis

imal models of renal disease

Outcome Refs

Functional and histologic protection,

blunted inflammation

Reviewed in [12]

Modified transcriptomic response to injury Reviewed in [12]

Functional and histologic protection,


[26]

tin D1 Blunted inflammation, amplified HO-1 [41]

, Functional and histologic protection,


[42]

Treatment of rat PMN ex vivo blunted their

trafficking into glomeruli

Reviewed in [12]

Blunted inflammation Reviewed in [12]

Functional protection, blunted inflammation Reviewed in [12]

Blunted inflammation [27]

Functional protection Reviewed in [12]

Vol. 4, No. 1 2007 Drug Discovery Today: Disease Mechanisms | Renal diseases

[9,12]. Pharmacological amplification of renal LXA4 circuits

in the kidney by systemic treatment with LXA4 analogs

attenuated PMN trafficking to the injured kidney and cyto-

kine/chemokine formation and restored renal function. The

consequence of modulating endogenous renal LXA4 produc-

tion is highlighted by two independent studies. A rat model

of antiglomerular basement nephritis demonstrated that

renal overexpression of human 15-lipoxygenase (ALOX15),

a key enzyme in the formation of LXA4 (Fig. 1), was reno-

protective [14]. By contrast, decreased renal LXA4 biosynth-

esis in P-selectin knockout mice was associated with

exaggerated neutrophil infiltration in a model of nephrotoxic

serum nephritis [15].

Figure 1. Resident renal lipid autacoids tip the balance by counterbalancing pro

15-LOX is a key enzyme in the formation of two distinct renal anti-inflammatory

the rapid formation of NPD1 and LXA4 and their multipronged inhibitory action

cells and pathways that lead to oxidative stress and apoptosis. These anti-inflam

apoptotic PMN, accelerating re-epithelialization and limiting fibrosis in renal injury

provides an endogenous amplification loop to control exacerbated renal inflam

Taken together, an impressive body of work on experi-

mental models of inflammatory diseases, which include acute

ischemic renal injury and glomerulonephritis (Table 1), have

clearly demonstrated that the endogenous LXA4 circuit is

important to counter-regulate proinflammatory pathways

and promote the resolution of inflammation. Hopefully, this

provides a solid foundation to finally move the therapeutic

use of LXA4 mimetics from bench to bedside.

Essential v-3 fatty acids protect the

cardiovascular-renal system

The importance of essential polyunsaturated fatty acids is

underscored by the well-established role of v-3 polyunsatu-

inflammatory signals and promoting the active resolution of inflammation.

lipid autacoids, DHA-derived NPD1 and AA-derived LXA4. Insult triggers

s target cytokines/chemokine formation, leukocyte trafficking, mesangial

matory actions are complimented by stimulating macrophages to remove

. A potential positive feedback loop with the cytoprotective HO-1 system

mation and ensure execution of the acute response.

www.drugdiscoverytoday.com 5


rated fatty acids in maintaining human health [16-18]. Epi-

demiological studies have demonstrated that consumption of

fish oils, which are enriched in eicosapentaenoic acid (EPA, v-

3 C20:5) and docosahexaenoic acid (DHA, v-3 C22:6), lowers

the incidence of inflammatory and autoimmune diseases

[19]. It is important to recognize that without marked dietary

supplementation, EPA concentrations in human tissues,

plasma and milk are very low. By contrast DHA, like AA, is

found in most human tissues, plasma and milk at concentra-

tions of 1–20% of total fatty acids [20]. Moreover, in the

cerebral cortex, sperm and retina, DHA is present at much

higher concentrations than AA [20]. It is apparent that DHA,

even in the absence of dietary supplementation, must have a

crucial role in human physiology; a molecular mechanism for

its inflammatory/immune regulatory and neuroprotective

actions is just beginning to unfold.

Several recent prospective studies have demonstrated a

significant association of higher plasma DHA with a decreased

risk of dementia and Alzheimer’s disease [21], lower levels of

circulating inflammatory markers [22] and reduced progres-

sion of coronary atherosclerosis in women with coronary

artery disease [23]. Hence, it is not surprising that population

studies and clinical trials have provided compelling evidence

that dietary fish oils, enriched in DHA, are cardio- and reno-

protective and that DHA, in particular, has anti-inflammatory

and immune regulatory actions [5,16,18,24,25]. Specifically,

experimental models have demonstrated that treatment with

DHA alone ameliorates ischemic acute renal failure and

attenuates mycotoxin-induced IgA nephropathy in mice

[26,27].

Experimental and clinical data provide a strong rationale

for using v-3 fatty acids as treatment in progressive renal

diseases where inflammation and glomerulosclerosis are key

features of the disease mechanism (Table 1). Meta-analysis of

randomized trials provides evidence that long-term treat-

ment with EPA and DHA improves renal function and lowers

the risk of death or end-stage renal disease in patients with

IgA nephropathy [5]. However, clinical studies with v-3 diet-

ary supplementation are inherently complicated by the

source of the v-3 fatty acids and control of the background

diet. Thus, many studies report heterogeneous results; for

example, a systematic review and meta-analysis failed to

demonstrate a consistent benefit of fish oil supplementation

in kidney transplantation [28].

The therapeutic potential of dietary v-3 fatty acids has not

been realized because, until recently, no clear mechanism

could account for either the beneficial therapeutic properties

or the dietary requirement of essential v-3 fatty acids, espe-

cially not for DHA. A prevailing notion is that one of the

major v-3 fatty acids in fish oils, EPA (v-3, C20:5), is a

competing substrate for AA (v-6, C20:4) in generating oxy-

genated v-3 fatty acids with structures similar to proinflam-

matory leukotrienes and prostaglandins, but with far less


potent bioactions. However, it is now well appreciated that

several AA-derived eicosanoids are not proinflammatory and,

quite the contrary, are essential for normal physiological

responses, regulation of vascular tone and resolution of

inflammation. Moreover, it is challenging to increase EPA

concentrations in tissues to a level where it would effectively

compete with AA as a substrate. More importantly, it provides

no mechanism of action for the structurally distinct and

abundant DHA (v-3, C22:6).

A molecular mechanism for the protective actions

of essential EPA and DHA

EPA and aspirin-triggered resolvins

The recent discovery of novel EPA- and DHA-derived lipid

autacoids provides a major breakthrough in understanding

how these essential v-3 fatty acids might mediate their ben-

eficial actions [11]. These novel v-3 lipid autacoids have been

termed resolvins because they were first identified in resol-

ving inflammatory exudates and, based on the substrate, they

belong to the RvE series that is derived from EPA or the RvD

series that is derived from DHA. These lipid autacoids exhibit

stereoselective actions in vivo, evoke their bioactions in the

nanogram range and, in many aspects, possess the anti-

inflammatory and proresolving actions of LXA4. RvE1 was

the first identified resolvin, whose biosynthesis is initiated by

aspirin-acetylated COX-2. Unlike other nonsteroidal anti-

inflammatory drugs, aspirin covalently modifies COX-2,

which inhibits the cyclooxygenase activity while retaining

the peroxidase activity of the enzyme. Hence, acetylated

COX-2 is still enzymatically active and generates the meta-

bolic intermediate 18R-hydroxy eicosapentaenoic acid (18R-

HEPE) that is rapidly converted by 5-lipoxygenase (5-LOX), a

prominent enzyme in activated PMN, to form 5S,12R,18R-

trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid (RvE1).

This potent anti-inflammatory lipid mediator exhibits stereo-

selective actions in vivo and in vitro, and a ligand-specific G-

protein-coupled receptor for RvE1 has recently been identi-

fied [11]. In addition to EPA, COX-2 can also utilize DHA as a

substrate and, analogous to the formation of RvE1, can

initiate the formation of trihydroxy resolvins from the meta-

bolic intermediate 17R-HDHA [11].

The relevance of an aspirin-triggered pathway is under-

scored by the fact that aspirin is present in many over-the-

counter remedies and is one of the most widely used drugs in

the world. Moreover, in a large randomized study, which

clearly demonstrated the cardiovascular benefits of v-3 diet-

ary supplementation, patients in both arms of the study took

aspirin daily [11,17]. However, it is important to recognize

that CYP450 enzymes, which are expressed in all tissues

especially the kidney, can generate R-hydroxy fatty acid from

both AA and EPA [29–34]. Thus, CYP450 enzymes could be a

significant endogenous source of metabolic intermediates for

the formation of both 15-epi-LXA4 and RvE1 and potentially


DHA-derived 17R-resolvins. Clearly, 15-epi-LXA4 can be gen-

erated in part by aspirin-independent pathways in vivo

[35,36]; whether this is also the case for RvE1 has not been

determined. This is especially relevant because all NSAIDS,

including aspirin, are counterindicated for renal diseases

because they can adversely affect renal function.

A resident 15-lipoxygenase pathway for formation of DHA-derived

lipid autacoids

It was essential to delineate ‘aspirin-independent’ biosyn-

thetic pathways for the formation of v-3 lipid autacoids to

substantiate that enzymatic formation of v-3 immune reg-

ulatory and anti-inflammatory autacoids provides a molecu-

lar mechanism for the beneficial properties of ‘fish oils’.

Several recent reports have identified endogenous formation

of a DHA-derived lipid mediator, 10R,17S-dihydroxy-docosa-

4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid in both humans and

rodents [11,37], which has been termed neuroprotectin D1

(NPD1) or protectin D1 (PD1). 15-lipoxygenase (15-LOX)

initiates biosynthesis of NPD1 (Fig. 1), which includes the

key intermediates, 17S-hydroperoxy-DHA and 16,17-epoxide

DHA, and its complete structure has recently been assigned

[11]. In addition, 17S-hydroperoxy-DHA is also a substrate for

the leukocyte 5-LOX, and in a mechanism analogous to

lipoxins and RvE1 formation, epoxidation and hydrolases

form several distinct 17S-resolvins that, based on the position

of the three hydroxyl groups and conjugation of double

bonds (triene or tetraene), have been termed RvD1, RvD2,

RvD3 and RvD4 [11].

Several independent laboratories have now reported endo-

genous formation of this novel class of DHA-derived lipid

autacoids, each with a specific and distinct structure that

probably confer potent and stereoselective bioactions

[11,37]. 15-LOX is an important enzyme that has well-docu-

mented roles in regulating physiological and pathophysiolo-

gical inflammatory/immune functions [10,38]. The enzyme is

highly expressed in epithelial cells and is one of the most

prominent inducible genes in human monocytes. Moreover,

15-LOX activity has been demonstrated in human and rat

glomeruli [39] and 12/15-LOX gene expression has been

demonstrated in rat collecting ducts [40]. However, it is impor-

tant to point out that 12-lipoxygenase (12-LOX) and 15-LOX

in humans are distinct, both in their expression and enzymatic

activity. By contrast, rodents do not express a lipoxygenase

enzyme that generates predominantly 15-HETE from AA.

Hence, data regarding the role of endogenous 15-LOX that

Figure 2. Dietary v-3 PUFA improve survival after ischemic renal injury. (A) Su

diet, a v-3-enriched fish oil diet or a v-3-deficient corn oil diet. (B) Profile of D

the kidney 24 h post ischemic injury. Lipid autacoids (v-3 blue font, v-6 black fo

(MDS SCIEX 3200 QTRAP) using multiple reaction monitoring for established


are based on experiments in rats or mice have to be interpreted

with caution.

Renal formation and renoprotective actions of

DHA-derived lipid autacoids

In vitro and in vivo experiments have demonstrated the ther-

apeutic potential of DHA- derived lipid autacoids [11,37].

Specifically, NPD-1 is neuroprotective in experimental

ischemic stroke, protects human retinal pigment epithelial

cells from oxidative stress-induced apoptosis and promotes

epithelial wound healing in the eye. Its anti-inflammatory

actions include attenuation of PMN recruitment in peritonitis

and eosinophil and T lymphocyte recruitment in aeroallergen-

challenged airways and formation of proinflammatory cyto-

kines/chemokines [11,37]. We have reported that NPD1 is

formed in the kidney and that systemic treatment with

NPD1 ameliorates inflammation in a mouse model of acute

ischemic renal injury [41]. The therapeutic potential of DHA-

derived lipid autacoids for treating renal diseases has been

demonstrated in a recent study [42]. In a model of renal

bilateral ischemic/reperfusion injury, mice were treated with

NPD1 or a mixture of 17S-resolvins (RvD1, RvD2 and RvD3).

Both treatment protocols reduced the number of infiltrating

PMN and blocked Toll-receptor-mediated activation of macro-

phages and interstitial fibrosis, while restoring renal function.

More importantly, the study also demonstrated the endogen-

ous formation of NPD1 and 17S-resolvins in the mouse kidney

and plasma without DHA treatment (Fig. 1).

The consequence of acutely modifying dietary intake of v-

3 and v-6 fatty acids on ischemic renal injury is highlighted

by recent results from our laboratory (Fig. 2). Mice that were

placed for 4–6 weeks on a corn oil diet, which is deficient in v-

3 fatty acids, did not survive severe renal ischemia (45 min).

By sharp contrast, mice on a standard rodent chow or on an

enriched fish oil diet had an 82% and 100% survival rate,

respectively. This striking protective effect of dietary v-3 fatty

acids correlated with amplified renal formation of both NPD1

and 17-HDHA (Fig. 2). These results [41] and reports from

other laboratories [11,37] strongly suggest that DHA-derived

autacoids are an endogenous and resident-protective path-

way in the kidney (Table 1), which complements the well-

established anti-inflammatory LXA4 circuit (Fig. 1). The pro-

resolving and anti-inflammatory actions of both NPD1 and

LXA4 in the kidney may in part be mediated by regulating the

expression of the established cytoprotective and antioxidant

heme-oxygenase (HO) system [43,44]. Heme-oxygenase gen-

rvival data 24 h post ischemic injury in mice placed on a standard rodent

HA- and AA-derived lipoxygenase metabolites formed endogenously in

nt) were analyzed by a triple quadruple linear ion trap LC/MS/MS system

transition ions. (C) MS/MS identification of NPD1.


erates two prominent protective mediators: (1) the anti-oxi-

dant, bilirubin; and (2) the bioactive gas, carbon monoxide,

which activates guanylate cyclase and regulates MAP kinase

pathways causing down-regulation of the proinflammatory

cytokines IL-6, TNFa, IL-1b and MIP-1a. It is important to

point out that numerous reports [9,11,13,37] have demon-

strated in vitro and in vivo that both LXA4 and NPD1 down-

regulate the same profile of proinflammatory cytokines, which

are the target for the protective action of carbon monoxide.

Studies have clearly demonstrated that pharmacological

amplification of HO-1 prevents the onset or progression of

acute kidney injury [43]. Therefore, it is of particular interest

that NPD1 as well as LXA4 amplifies expression of HO-1 in vitro

in vascular endothelial cells, epithelial cells, mesangial cells

and, in vivo in kidneys subjected to ischemic renal injury

[41,45,46]. Moreover, we recently found that the 15-LOX

and HO act in concert to control exacerbated inflammation

to promote epithelial wound healing in the eye [46]. Whether

this positive feedback loop for amplification of resident anti-

inflammatory signals is also present in the kidney has yet to be

determined, but it is of particular interest given the renopro-

tective role of both HO and 15-LOX systems.

Conclusion

Lipid autacoids, such as eicosanoids, play important roles in

renal physiology and, more importantly, are some of the

earliest signals triggered by injury and stress. Inflammation

is recognized as a major contributing factor to the pathophy-

siology of many renal diseases. It is now appreciated that vital

inflammation is a tightly regulated and balanced program,

which includes active pathways for the resolution of leuko-

cytes and the promotion of wound healing, to restore tissue

homeostasis. Targeting pathways that promote the resolution

of inflammation has emerged as a promising and novel

therapeutic strategy to fight inflammatory diseases. A rapidly

evolving field has identified the LXA4 circuit as an important

regulator for counterbalancing proinflammatory cascades

and the resolution of inflammation. Pharmacological and

genetic amplification of this endogenous pathway in the

kidney is renoprotective in experimental models of glomer-

ulonephritis and ischemic renal injury. A wealth of experi-

mental and human data, detailed structure–function studies

and development of analogs provide a compelling rationale

to evaluate lipoxin mimetics in clinical trials.

Clinical and experimental studies clearly demonstrate the

essential dietary requirement of v-3 fatty acids, especially

DHA, and more importantly, their cardio- and renoprotective

properties. Discovery of novel DHA- and EPA-derived lipid

autacoids provides a molecular mechanism for the immuno-

protective and anti-inflammatory actions of essential v-3 fatty

acids. Human and animal data have demonstrated endogen-

ous formation of a potent anti-inflammatory DHA-derived

autacoid, NPD1, in human lungs and brain as well as in mouse

kidneys. Dietary and therapeutic amplification of NPD1

restores renal function and limits fibrosis and inflammation

in models of ischemic renal injury. Recent reports suggest that

lipoxin and NPD1 may mediate their actions by amplifying the

expression of the renoprotective HO system, which suggests

that anti-inflammatory circuits may act in concert to regulate

acute and exacerbated inflammatory responses.

In summary, evidence strongly supports an important role

of resident lipid anti-inflammatory circuits in controlling

renal inflammation. Impaired activation of these protective

lipid circuits is likely to lead to a dysregulated inflammatory

response, transition to chronic inflammation and ultimately

progressive renal injury. Experimental models strongly sup-

port the efficacy of amplifying protective lipid circuits as a

novel approach to limit the sequelae of renal injury.

Acknowledgements

Research from the author’s laboratory that is included in this

review was sponsored by grants from the National Institutes

of Health (EY016136 and HL34300). We thank M. Steinberg

for editing and M. Laniado-Schwartzman for critical review

and helpful suggestions.

References1 Gilroy, D.W. et al. (2004) Inflammatory resolution: new opportunities for

drug discovery. Nat. Rev. Drug Discov. 3, 401–416

2 Kumar, V. et al. (2004) Robbins and Cotran Pathological Basis of Disease. W.B.

Saunders Company

3 Serhan, C.N. et al. (2007) Resolution of inflammation: state of the art,

definitions and terms. FASEB. J. 21, 325–332

4 Bonventre, J.V. and Zuk, A. (2004) Ischemic acute renal failure: an

inflammatory disease? Kidney Int. 66, 480–485

5 Donadio, J.V. and Grande, J.P. (2002) IgA nephropathy. N. Engl. J. Med.

347, 738–748

6 Singbartl, K. and Ley, K. (2004) Leukocyte recruitment and acute renal

failure. J. Mol. Med. 82, 91–101

7 Serhan, C.N. and Savill, J. (2005) Resolution of inflammation: the

beginning programs the end. Nat. Immunol. 6, 1191–1197

8 Imig, J.D. (2006) Eicosanoids and renal vascular function in diseases. Clin.

Sci. (Lond.) 111, 21–34

9 McMahon, B. and Godson, C. (2004) Lipoxins: endogenous regulators of

inflammation. Am. J. Physiol. Renal Physiol. 286, F189–F201

10 Chiang, N. et al. (2006) The lipoxin receptor ALX: potent ligand-specific

and stereoselective actions in vivo. Pharmacol. Rev. 58, 463–487

11 Serhan, C.N. (2006) Resolution phases of inflammation: novel

endogenous anti-inflammatory and proresolving lipid mediators and

pathways. Annu. Rev. Immunol. 25, 101–137

12 Kieran, N.E. et al. (2004) Lipoxins: potential anti-inflammatory,

proresolution, and antifibrotic mediators in renal disease. Kidney Int. 65,

1145–1154

13 Parkinson, J.F. (2006) Lipoxin and synthetic lipoxin analogs: an overview

of anti-inflammatory functions and new concepts in immunomodulation.

Inflamm. Allergy Drug Targets 5, 91–106

14 Munger, K.A. et al. (1999) Transfection of rat kidney with human 15-

lipoxygenase suppresses inflammation and preserves function in

experimental glomerulonephritis. Proc. Natl. Acad. Sci. U. S. A. 96, 13375–

13380

15 Mayadas, T.N. et al. (1996) Acute passive anti-glomerular basement

membrane nephritis in P-selectin-deficient mice. Kidney Int. 49, 1342–1349

16 De Caterina, R. et al. eds (1993) n � 3 Fatty acids and Vascular Disease,

Springer-Verlag



17 Investigators, G-P. (1999) Dietary supplementation with n � 3

polyunsaturated fatty acids and vitamin E after myocardial infarction:

results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della

Sopravvivenza nell’Infarto miocardico. Lancet 354, 447–455

18 Simopoulos, A.P. et al. (1999) Workshop on the essentiality of an

recommended dietary intakes for omega-6 and omega-3 fatty acids. J. Am.

Coll. Nutr. 18, 487–489

19 Kromann, N. and Green, A. (1980) Epidemiological studies in the

Upernavik district, Greenland. Incidence of some chronic diseases 1950–

1974. Acta Medica Scandinavica 208, 401–406

20 Arterburn, L.M. et al. (2006) Distribution, interconversion, and dose

response of n � 3 fatty acids in humans. Am. J. Clin. Nutr. 83 (6 Suppl.),

1467S–1476S

21 Schaefer, E.J. et al. (2006) Plasma phosphatidylcholine docosahexaenoic

acid content and risk of dementia and Alzheimer disease: the Framingham

heart study. Arch. Neurol. 63, 1545–1550

22 Ferrucci, L. et al. (2006) Relationship of plasma polyunsaturated fatty acids

to circulating inflammatory markers. J. Clin. Endocrinol. Metab. 91, 439–

446

23 Erkkila, A.T. et al. (2006) Higher plasma docosahexaenoic acid is associated

with reduced progression of coronary atherosclerosis in women with CAD.

J. Lipid Res. 47, 2814–2819

24 Mori, T.A. (2006) Omega-3 fatty acids and hypertension in humans. Clin.

Exp. Pharmacol. Physiol. 33, 842–846

25 Donadio, J.V. and Grande, J.P. (2004) The role of fish oil/omega-3 fatty

acids in the treatment of IgA nephropathy. Semin Nephrol. 24, 225–243

26 Kielar, M.L. et al. (2003) Docosahexaenoic acid ameliorates murine

ischemic acute renal failure and prevents increases in mRNA abundance

for both TNF-alpha and inducible nitric oxide synthase. J. Am. Soc. Nephrol.

14, 389–396

27 Jia, Q. et al. (2004) Docosahexaenoic acid and eicosapentaenoic acid, but

not alpha-linolenic acid, suppress deoxynivalenol-induced experimental

IgA nephropathy in mice. J. Nutr. 134, 1353–1361

28 Tatsioni, A. et al. (2005) Effects of fish oil supplementation on kidney

transplantation: a systematic review and meta-analysis of randomized,

controlled trials. J. Am. Soc. Nephrol. 16, 2462–2470

29 Keeney, D.S. et al. (1998) Differentiating keratinocytes express a novel

cytochrome P450 enzyme, CYP2B19, having arachidonate

monooxygenase activity. J. Biol. Chem. 273, 32071–32079

30 Bylund, J. et al. (1998) Analysis of cytochrome P450 metabolites of

arachidonic and linoleic acids by liquid chromatography–mass

spectrometry with ion trap MS. Anal. Biochem. 265, 55–68


31 Barbosa-Sicard, E. et al. (2005) Eicosapentaenoic acid metabolism by

cytochrome P450 enzymes of the CYP2C subfamily. Biochem. Biophys. Res.

Commun. 329, 1275–1281

32 Lauterbach, B. et al. (2002) Cytochrome P450-dependent

eicosapentaenoic acid metabolites are novel BK channel activators.

Hypertension 39 (2 Pt 2), 609–613

33 Schwarz, D. et al. (2005) Human CYP1A1 variants lead to differential

eicosapentaenoic acid metabolite patterns. Biochem. Biophys Res. Commun.

336, 779–783

34 Choudhary, D. et al. (2004) Metabolism of retinoids and arachidonic acid

by human and mouse cytochrome P450 1b1. Drug Metab. Dispos. 32, 840–

847

35 Titos, E. et al. (1999) Hepatocytes are a rich source of novel aspirin-

triggered 15-epi-lipoxin A(4). Am. J. Physiol. 277 (5 Pt 1), C870–C877

36 Chiang, N. et al. (2004) Aspirin triggers antiinflammatory 15-epi-lipoxin

A4 and inhibits thromboxane in a randomized human trial. Proc. Natl.

Acad. Sci. U. S. A. 101, 15178–15183

37 Bazan, N.G. (2006) Cell survival matters: docosahexaenoic acid signaling,

neuroprotection and photoreceptors. Trends Neurosci. 29, 263–271

38 Kuhn, H. and O’Donnell, V.B. (2006) Inflammation and immune

regulation by 12/15-lipoxygenases. Prog. Lipid. Res. 45, 334–356

39 Sraer, J. et al. (1983) Metabolism of arachidonic acid via the lipoxygenase

pathway in human and murine glomeruli. J. Biol. Chem. 258, 4325–4330

40 Reinhold, S.W. et al. (2006) Gene expression of 5-, 12-, and 15-

lipoxygenases and leukotriene receptors along the rat nephron. Am. J.

Physiol. Renal Physiol. 290, F864–F872

41 Hassan, I.R. and Gronert, K. (2006) 15-Lipoxygenase and docosahexaenoic

acid derived lipid mediators ameliorate inflammation and augment heme

oxygenase-1 expression in acute renal failure. Prostagland. Other Lipid

Mediat. 79, 158

42 Duffield, J.S. et al. (2006) Resolvin D series and protectin D1 mitigate acute

kidney injury. J. Immunol. 177, 5902–5911

43 Abraham, N.G. and Kappas, A. (2005) Heme oxygenase and the

cardiovascular–renal system. Free Radic. Biol. Med. 39, 1–25

44 Ryter, S.W. et al. (2006) Heme oxygenase-1/carbon monoxide: from basic

science to therapeutic applications. Physiol. Rev. 86, 583–650

45 Nascimento-Silva, V. et al. (2005) Novel lipid mediator aspirin-triggered

lipoxin A4 induces heme oxygenase-1 in endothelial cells. Am. J. Physiol.

Cell Physiol. 289, C557–C563

46 Biteman, B. et al. Interdependence of lipoxin A4 and heme-oxygenase in

counterregulating inflammation during corneal wound healing. FASEB J.

(in press)

reaping the benefits of renal protective lipid autacoids

Documents