Scholarly article on topic 'Resolution of inflammation: therapeutic potential of pro-resolving lipids in type 2 diabetes mellitus and associated renal complications'

Resolution of inflammation: therapeutic potential of pro-resolving lipids in type 2 diabetes mellitus and associated renal complications Academic research paper on "Biological sciences"

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Academic research paper on topic "Resolution of inflammation: therapeutic potential of pro-resolving lipids in type 2 diabetes mellitus and associated renal complications"

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published: 18 October 2012 doi: 10.3389/fimmu.2012.00318

Resolution of inflammation: therapeutic potential of pro-resolving lipids in type 2 diabetes mellitus and associated renal complications

Emma Borgeson and Catherine Godson*

UCD Diabetes Research Centre, UCD Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland

Edited by:

Janos G. Fiiep, University of Montreal, Canada

Reviewed by:

Pabio Peiegrin, Fundación Formacion Investigación Sanitaria Region Murcia -Hospital Universitario Virgen Arrixaca, Spain

Masato Kubo, Research Institute for Biological Science, Tokyo University of Science, Japan


Catherine Godson, UCD Diabetes Research Centre, UCD Conway Institute, Schooi of Medicine and Medical Sciences, University College Dubiin, Dubiin, Ireiand. e-maii:

The role of inflammation in the pathogenesis of type 2 diabetes mellitus (T2DM) and its associated complications is increasingly recognized. The resolution of inflammation is actively regulated by endogenously produced lipid mediators such as lipoxins, resolvins, protectins, and maresins. Here we review the potential role of these lipid mediators in diabetes-associated pathologies, specifically focusing on adipose inflammation and diabetic kidney disease, i.e., diabetic nephropathy (DN). DN is one of the major complications of T2DM and we propose that pro-resolving lipid mediators may have therapeutic potential in this context. Adipose inflammation is also an important component of T2DM-associated insulin resistance and altered adipokine secretion. Promoting the resolution of adipose inflammation would therefore likely be a beneficial therapeutic approach inT2DM.

Keywords: inflammation, resolution, lipxoins, resolvins, protectins, renal inflammation


The inflammatory response is necessary for effective host defense, although it must eventually dissipate to ensure tissue homeostasis and avoid pathologic conditions such as abscess formation, scarring, fibrosis, and eventual organ failure (Lawrence and Gilroy, 2007). Indeed, compromised resolution has been proposed as an underlying mechanism in many prevalent chronic diseases such as arthritis, diabetes, and atherosclerosis (Serhan etal., 2008; Maderna and Godson, 2009). It is now recognized that the resolution of inflammation is a dynamically regulated process orchestrated by mediators that play important counter-regulatory roles including cytokines, chemokines, and lipid mediators such as the lipoxins (LXs), resolvins, and protectins (Serhan, 2009). These mediators reduce vascular permeability and inhibit polymor-phonuclear cell (PMN) recruitment, while promoting recruitment of monocytes and stimulating efferocytosis (Serhan etal., 2008). It has also been proposed that pro-resolving lipids stimulate lymphatic drainage of leukocytes (Arita etal., 2005b). Interestingly, the signaling pathways initially inducing prostaglandin

Abbreviations: ACE inhibitors, angiotensin-converting-enzyme inhibitors; AIM, antioxidant inflammation modulator; ARBs, angiotensin receptor blockers; ATMs, adipose tissue M^s; CKD, chronic kidney disease; CLS, crown like structures; CRP, C-reactive protein; DHA, docosahexaenoic acid; DN, diabetic nephropathy; eGFR, estimated glomerular filtration rate; EPA, eicosapentaenoic acid; HUVECs, human umbilical vein endothelial cells; IL, interleukin; LO, lipoxygenase; LXA4, lipoxin A4 (S),6(R),15,Trihydroxyeicosa-7E,9E,11Z,13E-tetraenoic acid; M.tb, Mycobacterium tuberculosis; maresins, MO mediators in resolving inflammation; miRNA, micro RNA; M^, macrophages; PG, prostaglandin; PMN, polymorphonuclear cell; RA, rheumatoid arthritis; RAS, renin-angiotensin system; Rvs, resolvins; T2DM, type 2 diabetes mellitus; UUO, unilateral ureteric obstruction.

(PG)E2 and PGD2 formation and thus the onset of inflammation, may actively switch the production of lipid mediators from pro-inflammatory to pro-resolving by inducing 5-lipoxygenases (LO) necessary for production of LXs, protectins, and resolvins (Serhan and Savill, 2005). In this way physiological inflammation programs its own resolution and promotes tissue homeostasis (Levy etal., 2001).


The LXs are produced endogenously at sites of inflammation as counter-regulatory lipid mediators with anti-inflammatory, pro-resolving, and anti-fibrotic bioactions (Serhan etal., 2008; Maderna and Godson, 2009). LXs are typically generated by tran-scellular metabolism between neutrophils, platelets, and resident tissue cells, such as epithelial cells (Lefer et al., 1988; Serhan, 2007), through the sequential action of 5-LO and either 12-LO or 15-LO (Serhan, 2005; Parkinson, 2006). LXs limit leukocyte chemotaxis (Lee etal., 1989) and activation of neutrophils and eosinophils (Bandeira-Melo etal., 2000), while stimulating M^> efferocytosis of apoptotic cells (Godson etal., 2000; Mitchell etal., 2002; Reville etal., 2006). Lipoxin A4 (LXA4) and its positional isomer lipoxin B4 (LXB4) are the principal LX species found in mammals. Although the LXB4 receptor remains to be identified, the LXA4 receptor FPR2/ALX is expressed on cells of diverse lineage, including fibroblasts (Wu etal., 2006a), renal mesangial cells (McMahon etal., 2002; Mitchell etal., 2004), and epithelial cells (Nascimento-Silva etal., 2007). LXs are protective in several experimental models of disease, e.g., inflammatory bowel diseases (Fiorucci et al., 2004), periodontal disease (Serhan, 2004; Kantarci and Van Dyke, 2005; Kantarci etal., 2006), and cardiovascular

disease (Serhan, 2005). LXs have also been reported to act as vasodilators (von der Weid et al., 2004) and may reprogram M^s from a classically activated (M1) phenotype to a spectrum of alternative activation (Mitchell et al., 2002). The bioactions of LXs are summarized in Table 1. The impact of LXs in maintaining the exquisite equilibrium between effective host defense and home-ostasis is remarkably illustrated by the fact that over production of LXs may compromise host defense to pathogens. In the case of Mycobacterium tuberculosis (M.tb), increased LXA4 production is

associated with decreased TNF-a activity and results in an inadequate inflammatory response (Tobin etal., 2010). Conversely, LXA4 increases survival rate in Toxoplasma gondii infection where a compromised immune response due to diminished LO activity and LXbiosynthesis is detrimental (Aliberti, 2005).


The principal LXA4 receptor is FPR2/ALX, which has been identified and cloned in numerous cell types, including monocytes

Table 1 | Lipoxin induced bioactions.

Cell type Bioactions in vitro

LXA4, LXA4-analogs and aspirin-triggered lipoxins (ATLs)

Monocytes Macrophages



T cells





Mesangial cells

GI epitlelium (enterocytes)

Hepatocytes Astrocytoma cells

Stimulate chemotaxis and adhesion without causing ROS production (Maddox and Serhan, 1996)

Stimulate efferocytosis while reducing inflammatory cytokine secretion (IFN-y and IL-6) and increasing pro-resolving cytokine

secretion (IL-10) (Mitchell etal., 2002; Schwab etal., 2007)

Switch M^ phenotype from inflammatory to pro-resolving

Inhibit chemotaxis, adhesion, and transmigration (Chiang etal., 2006).

Inhibit pro-inflammatory cytokine secretion (Jozsef etal., 2002)

Inhibit ROS production (Levy etal., 1999; Borgeson etal., 2010)

Enhance CCR5 expression on apoptotic PMN (Ariel etal., 2006)

Attenuate P-selectin-mediated PMN-endothelial cell interactions (Papayianni etal., 1996) Regulated as monocytes differentiate into DCs Yang etal., 2001) Trigger SOCS-2 expression (Machado etal., 2006)

Inhibit chemotaxis, IL-5, and eotaxin secretion (Soyombo etal., 1994; Bandeira-Melo etal., 2000; Levy etal., 2002)

Inhibit Porphyromonas gingivalis-induced aggregation (Borgeson etal., 2010)

Inhibit anti-CD3Ab induced TNF-a (Ariel etal., 2003)

Block cytotoxicity (Ramstedt etal., 1985, 1987)

Inhibit anti-CD3Ab induced TNF-a (Ariel etal., 2003)

Inhibit P-selectin mobilization (Scalia etal., 1997)

Upregulate IL-10 while inhibiting LTD4 andVEGF stimulated proliferation and angiogenesis (Baker etal., 2009)

Inhibit TNF-a induced IL-8 (Bonnans etal., 2007)

Inhibit epithelial to mesenchymal transition (Wu etal., 2010)

Inhibit proliferation (Wu etal., 2006a)

Inhibit IL-10 induced IL-6, IL-8, and MMP-3 (Sodin-Semrl etal., 2000)

Inhibit inflammatory cytokine production (Wu etal., 2006b), proliferation and cell cycle progression (Badr etal., 1989; Mitchell etal., 2004, 2007; Wu etal., 2005, 2006b) as well as ROS production (Mitchell etal., 2007)

AntagonizeTNF-a stimulated neutrophil-enterocyte interactions in vitro and attenuateTNF-a chemokine release and colonocyte

apoptosis in human intestinal mucosa ex vivo (Goh etal., 2001 )

Inhibit TNF-a induced IL-8 (Gewirtz etal., 2002)

Reduce PPARa and CINC-1 expression (Planaguma etal., 2002)

Inhibit IL-10 induced IL-8 and ICAM-1 expression (Decker etal., 2009)

LXB4 and LXB4-analogs

Monocytes Stimulate monocytes recruitment, chemotaxis and adherence without causing ROS production (Maddox and Serhan, 1996)

Increase adherence of undifferentiated THP-1 to laminin (Maddox etal., 1998) PBMC Inhibit anti-CD3 Ab inducedTNF-a (Ariel etal., 2003)

PMN Inhibit PMN migration across endothelium (HUVEC monolayer; Maddox etal., 1998)

Attenuate P-selectin-mediated PMN-endothelial cell interactions (Papayianni etal., 1996) NK cells Inhibit cytotoxicity (Ramstedt etal., 1985)

and M^s (Maddox etal., 1997), T cells (Ariel etal., 2003), synovial fibroblasts (Sodin-Semrl etal., 2000), renal mesangial cells (McMahon etal., 2002), and enterocytes (Gronert etal., 1998). In contrast to conventional GPCRs, which typically show very specific ligand binding, the FPR2/ALX receptor binds pleiotropic ligands, both lipids and small peptides, such as acute phase proteins (Chiang etal., 2000), and may elicit ligand-dependent pro-inflammatory or anti-inflammatory responses (Chiang etal., 2006; Maderna and Godson, 2009). Krishnamoorthy et al. (2010) recently found that LXA4 also interacts with another G-protein coupled receptor, namely GPR32.

LXA4 undergoes rapid inactivation in vivo, primarily by PG dehydrogenase-mediated oxidation and reduction (Serhan etal., 1995) and efforts have been made to design chemically stable LX analogs. Because the three-dimensional molecular structure of the FPR2/ALX receptor is as of yet unknown, designing LXA4 analogs is based on experimentally discovered structure/function relationship of LXA4. The LXA4 molecule can be considered in three regions; the lower chain, the upper chain, and the tetraene side chain (Duffy and Guiry, 2010). The first generation LXA4 analogs carry modifications in the lower alkyl chain, to increase metabolic stability and prevent oxidation (Clish et al., 1999). The second generation analogs are collectively referred to as 3-oxa-LXA4 and were constructed carrying modifications in the upper chain (Petasis etal., 2005), replacing the C3 methylene group with an oxygen molecule (Guilford and Parkinson, 2005). The third generation LXA4 analogs are characterized by replacement of the triene structure with a benzene ring (O'Sullivan et al., 2007; Petasis etal., 2008). Importantly, the o-[9,12]-Benzo-15-epi-LXA4 has been shown to activate the FPR/ALX receptor in a similar manner to native LXA4, using an engineered P-arrestin system (Sun etal., 2009).


Resolvins, protectins, and maresins are pro-resolving lipids discovered by Serhan etal. (2000) through sophisticated lipidomic analysis of resolution phase exudates in the murine dorsal air pouch model. Resolvins may be divided into the E series (RvEs) and D series (RvDs), which are generated from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, the most common forms of w-3 PUFA. Similarly, protectins and maresins are generated from DHA. Like the LXs, resolvins are generated in a transcellular manner by the sequential action of LO. Protectins and maresins on the other hand are generated by single cells, but also through the action of LO. In neutrophils RvE1 has been shown to bind the GPCR LTB4 receptor BLT1 with a Kd of 45 nM (Arita etal., 2007), whereas in M^ and dendritic cells RvE1 bind ChemR23 with a Kd of 11.3 ± 5.4 nM and Bmax indicating approximately 4,200 binding sites per cell (Arita et al., 2005b; Kohli and Levy, 2009). RvD1 has also been reported to interact both with FPR2/ALX and GPR32 in phagocytes (Krishnamoorthy etal., 2010). As of yet it is not entirely clear which receptor the protectins and maresins act through, although PD1 has a high affinity surface binding site on human PMN and retinal pigment epithelium cells (Bannenberg and Serhan, 2010). Resolvins, protectins, and maresins all display potent anti-inflammatory and pro-resolving effects inhibiting production of pro-inflammatory

mediators, regulating neutrophil trafficking and promoting effe-rocytosis (Schwab etal., 2007; Serhan, 2009). The effects of these lipid mediators are summarized in Table 2.


Diabetes mellitus (DM) is a serious metabolic disorder of glucose homeostasis reflecting destruction of the P-cells of the pancreas and subsequent lack of insulin production (type 1 DM, T1DM) or decreased target organ sensitivity to insulin and P-cell dysfunction (type 2 DM, T2DM). T2DM is defined as having a fasting plasma glucose >7.0 mmol/l and affects over 90% of diabetics, or an estimated 285 million people globally (Cusi, 2010). T2DM imposes significant socioeconomic burdens through its many diabetes-associated complications. These can be divided into microvascular complications [diabetic nephropathy (DN), neuropathy, and retinopathy] and macrovascular complications [atherosclerosis, ischemic heart disease, stroke, and peripheral vascular disease often resulting in amputations] (Wild etal., 2004). Risk factors of T2DM include genetic preposition, ethnicity, high blood pressure, and high cholesterol, but obesity is frequently cited as the primary cause.

The role of inflammation in diabetes is becoming more evident and elevated circulating interleukin (IL)-1p, IL-6, and C-reactive protein (CRP) are predictive of T2DM (Navarro and Mora, 2006; de Luca and Olefsky, 2008; Donath and Shoelson, 2011). These inflammatory markers are primarily derived from the adipose tissue and the liver. The hypothesis that the pathogenesis of T2DM reflects an inflammatory disorder is supported by pre-clinical studies and clinical trials using anti-inflammatory agents (Donath and Shoelson, 2011). Examples of these include IL-1p receptor blockers, anti-TNF-a and IL-6 therapies, as well as the use of salsalate. We will now briefly discuss current attempts to use anti-inflammatory therapeutics to attenuate the pathology of diabetes.

Interleukin-1P is a key regulator of inflammation both in T1DM and T2DM and has been shown to induce pancreatic P-cell apoptosis and exacerbate the systemic inflammation associated with diabetes, for instance by augmenting adipocyte TNF-a and IL-6 production (Akash et al., 2012). Patients with T2DM display increased IL-1p levels (Boni-Schnetzler etal., 2008), while its naturally occurring IL-1 receptor antagonist (IL-1Ra) is diminished (Maedler etal., 2004). Interest has been directed toward using IL-1Ra as a therapeutic in T2DM. Clinical trials show that the IL-1Ra anakinra improves glycemia and P-cell secretory functions, while attenuating systemic inflammation (Donath and Shoelson, 2011). For instance, anakinra administered over a 13-week period in T2DM patients increased insulin production, while glycosy-lated hemoglobin, i.e., HbA1c and the inflammatory marker CRP were significantly reduced (Larsen et al., 2007). The limitation with IL-1Ra lies in its short half-life, but successful attempts have been made to increase its stability by fusing IL-1Ra with peptides such as human serum albumin (HLA) or elastin-like polypeptides (ELPs), although these compounds remain to be tested in diabetic models (Akashetal., 2012).

TNF-a is also implicated in the pathogenesis of insulin resistance (IR) and its expression correlates with reduced insulin-stimulated glucose disposal (Kern etal., 2001). TNF-a is elevated

Table 2 | Resolvin, protectin, and maresin induced bioactions.

Cell type Bioactions in vitro

Resolvin E1

Macrophages Stimulates efferocytosis while reducing IFN-y and IL-6 (Schwab etal., 2007)

PMN Decreases transendothelial and epithelial migration (Campbell etal., 2007)

Stimulates L-selectin shedding, while reducing CD18 expression and inhibiting PMN rolling in vivo (Dona etal., 2008) Attenuates BLT1 dependedTNF-a and NF-kB activation (Arita etal., 2007) Enhances CCR5 expression on apoptotic PMN (Ariel etal., 2006) Dendritic cells Inhibits migration (Arita etal., 2005a)

Reduces IL-12 production from DCs stimulated with pathogen extract (Arita etal., 2005a) Platelets Disruptes platelet aggregation (Dona etal., 2008; Fredman etal., 2010)

Resolvin D1

Microglia cells Inhibits IL-1ß expression (Serhan etal., 2002)

Protectin D1

PMN Enhances CCR5 expression on apoptotic PMN (Ariel etal., 2006)

Mф Stimulates efferocytosis while reducing IFN-y (Schwab etal., 2007)

T cell Promotes apoptosis, inhibits TNF-a and IFN-y (Ariel etal., 2005)

Glia cells Reduces IL-1 ß-induced NF-kB activation and COX2 expression (Marcheselli etal., 2003), reduces amyloid ß-42-induced nerotoxicity,

promotes amyloid ß-induced apoptosis (Lukiw etal., 2005) Epithelium Protects from apoptosis induced by oxidative stress (Mukherjee etal., 2004)

Maresin 1

Macrophage Stimulates efferocytosis (Serhan etal., 2009)

both in obese rodents (Uysal etal., 1997) and obese humans (Hotamisligil etal., 1995; Kern etal., 2001) and furthermore decreases upon weight loss (Kern etal., 1995). TNF-a-/- ob/ob mice have significantly improved insulin sensitivity (Uysal etal., 1997) and obese mice lacking the TNF-a receptor are protected from high fat diet induced IR (Romanatto etal., 2009). However, in humans TNF-a neutralizing antibodies does not appear to improve insulin sensitivity in obese subjects (Ofei etal., 1996; Rosenvinge etal., 2007). Nevertheless, TNF-a blockers are often used to treat rheumatoid arthritis (RA) and it was recently reported that obese RA patients receiving TNF-a blockers displayed improved fasting glucose and increased circulating adiponectin levels (Stanley et al., 2010), possibly warranting more studies in the field. IL-6 is also an important inflammatory mediator in diabetes and increased levels correlate with IR (Pradhan etal., 2001), although it appears to have a dual role. Whereas IL-6 causes IR in adipocytes (Rotter etal., 2003) and anti-IL-6 therapy over a 6 month period diminished HbA1c in diabetic RA patients (Ogata etal., 2011), the IL-6 derived from skeletal muscle during exercise appears beneficial (Pedersen etal., 2003). The use of anti-IL-6 blockers as an anti-inflammatory therapeutic in diabetes has therefore been debated. Salsalate on the other hand is a very interesting drug in the context of diabetes and has been shown to reduce CRP, FFA, and triglycerides while increasing insulin sensitivity and adiponectin levels (Koska et al., 2009; Goldfine etal., 2010). Salsalate may, however, cause gastric irritation and should be used with caution in pregnancy (Torloni et al., 2006; Chyka et al., 2007). Collectively these studies indicate

the potential of using anti-inflammatory therapeutics to attenuate T2DM.


There is a growing appreciation that adipose tissue is not merely an insulating energy store but is actually an endocrine organ regulating appetite, glucose and lipid metabolism, blood pressure, inflammation, and immune function (Kershaw and Flier, 2004). Adipose tissue has been shown to play a particularly important role in the systemic inflammation associated with obesity, IR, and diabetes. Factors such as prolonged obesity or aging cause a state of systemic low-grade inflammation, which induces mono-cyte recruitment to the adipose tissue. Adipose tissue is a source of pro-inflammatory cytokines and adipose tissue M^> (ATM) derived TNF-a, IL6, and IL-1p contribute to adipose IR and exacerbates systemic inflammation (Lumeng et al., 2007b). Promoting resolution of adipose inflammation would likely be a beneficial therapeutic approach, reducing the risk of developing obesity-associated complications, such as IR and T2DM (Donath and Shoelson, 2011).

Given the spectrum of anti-inflammatory and pro-resolution bioactions of LXs and other counter-regulatory lipid mediators, these may provide a potential intervention to attenuate adipose inflammation (Gonzalez-Periz and Claria, 2010). We recently reported a role of LXA4 in adipose inflammation, culturing adipose explants of aging mice as an ex vivo model of adipose inflammation (Borgeson etal., 2012). We confirmed that LXA4

increased expression of critical components of insulin sensitivity, including the glucose transporter GLUT-4 and IRS-1, consistent with restoring insulin sensitivity in the tissue. Furthermore, LXA4 decreased IL-6 secretion while increasing production of the pro-resolving IL-10, suggesting that LXA4 acted in a pro-resolving manner (Börgeson etal., 2012). Indeed, IL-10 inversely correlates with T2DM and has been shown to inhibit IL-6-induced IR, attenuate MCP-1 secretion, and promote GLUT-4 and IRS-1 expression (Lumeng etal., 2007a; Gonzalez-Periz and Claria,

2010). The study also demonstrated that LXA4 partially rescued M®-inhibited adipose glucose uptake in vitro (Börgeson etal., 2012). Inflammatory M®s are a key component of augmented adipose IR (Lumeng et al., 2007b; Cusi, 2010; Spencer et al., 2010). Importantly, LXA4-mediated reversal of insulin desensitization correlated with restored adipose Akt activation, which is necessary for translocation of the glucose sensitizing GLUT-4 receptor from the cytosol to the plasma membrane (Börgeson et al., 2012). Interestingly, RvD1 also increased insulin-stimulated pAkt in adipose tissue of obese db/db mice (Hellmann etal., 2011). Furthermore, LXA4 inhibited M® TNF-a production, which is an important cytokine previously demonstrated to inhibit adipose glucose uptake in vitro (Gao etal., 2003). LXA4 also inhibited MCP-1 secretion, though the importance of MCP-1 in adipose inflammation has been debated (Chen etal., 2005; Inouye etal., 2007). The reduction of inflammatory cytokines may suggest that LXA4 promoted restoration of insulin sensitivity by altering M® phe-notype toward resolution. Finally, LXA4 also appeared to have a direct impact on adipocytes as it rescued TNF-a-induced desensitization to insulin-stimulated Akt activation, which also correlated with increased GLUT-4 translocation.

The beneficial effects of w-3 PUFA, RvE1, and PD1 have also been shown in ob/ob mice (Gonzalez-Periz etal., 2009). Both w-3 PUFA enriched diet and intraperitoneal injections of RvE1 increased expression of genes involved in glucose transport (GLUT-4) and insulin signaling (IRS-1), as well as genes involved in insulin sensitivity (PPARy). Similar to w-3 PUFA, RvE1 increased adiponectin levels, as did PD1 when incubated with adipose explants from ob/ob mice (Gonzalez-Periz etal., 2009). Additional studies show that RvD1 decrease accumulation of ATMs and improve insulin sensitivity while reducing fasting blood glucose in db/db diabetic mice (Hellmann etal.,

2011). Interestingly, the total number of ATMs remained unaltered with RvD1 treatment, but the ratio of M2:M1 increased. The number of adipose crown like structures (CLS) in obese animals was also reduced by 50-60% (Hellmann etal., 2011) and RvD1 significantly increased circulating adiponectin and adipose phosphorylation of AMPK. The study also reports diminished IL-6 secretion (Hellmann etal., 2011), which has previously been shown to suppress adiponectin in 3T3-L1 adipocytes (Fasshauer et al., 2003) and may explain the restored adiponectin levels, which in turn have been shown to increase insulin sensitivity (Kristiansen and Mandrup-Poulsen, 2005; Kadowaki et al., 2006).


Diabetic nephropathy presents a particularly important problem as it develops in 25-40% of diabetic patients and is the major cause of end-stage kidney disease (Ritz etal., 1999). DN is a type

of chronic kidney disease (CKD) rising in prevalence in concert with chronic DM in susceptible individuals. In addition to being the leading cause of renal failure, T2DM is also an independent risk factor in the development of cardiovascular disease (Syed and Khan, 2011). DN reflects the convergence of inflammatory, metabolic, and hemodynamic factors. Inflammation causes glomerulosclerosis, tubular atrophy, damage to renal vasculature, and fibrosis (Ferenbach etal., 2007). Renal matrix accumulation arises in response to paracrine and autocrine mediators produced by resident and infiltrating cells, such as mesangial cells and M^s.

Promoting inflammatory resolution is likely an attractive approach when trying to prevent renal fibrosis and CKD (Borgeson and Godson, 2010). The mechanisms by which resolution of renal inflammation occurs naturally and how they are subverted in disease are only beginning to be understood. Important components include efferocytosis of apoptotic cells and a change of the cytokine milieu from pro-inflammatory to anti-inflammatory/pro-resolving (Ferenbach et al., 2007; Borgeson and Godson, 2010). Biphasic regulation of renal inflammation and NF-kB also appears important, where the first peak mediated through p65/p50 heterodimers induces inflammation through pro-inflammatory mediators such as MCP-1 and RANTES. The second peak on the other hand (p50/p50 homodimers) promotes resolution by downregulating MCP-1/CCL1, RANTES/CCL5, and TNF-a (Panzer etal., 2009), while inducing expression of pro-resolving IL-10 (Cao etal., 2006). Similarly, to other pathologies it also appears that the phenotype of M^s is important in CKD (Wada etal., 2004; Sung etal., 2007). Whereas M1 M^s are detrimental, the M2a and perhaps even more so the M2c phenotype is beneficial (Wang and Harris, 2011).

M^s play an important role in DN as previously reported by Tesch (2008, 2010). M^s increase production of ROS, proinflammatory cytokines, and pro-fibrotic growth factors that contribute to the formation of myo-fibroblasts. M^s also appear to directly activate fibroblasts to a pro-fibrotic (myo-fibroblast) phenotype through secretion of galectin-3 (Henderson etal., 2008). Inhibition of M^> recruitment has been suggested to attenuate disease in several models of renal fibrosis with varying efficacy (Wada etal., 2004; Sung etal., 2007). For instance, MCP-1-/-mice are protected against renal injury in a model of T1DM (Chow etal., 2006) and furthermore urinary levels of MCP-1 are predictive of renal injury in humans and have been proposed as a diagnostic marker of progressive diabetic kidney disease (Tesch, 2008). There is a growing appreciation that the plasticity of M^s is an important factor in disease progression (Duffield, 2011; Wang and Harris, 2011) and that M^s also contribute to the resolution of renal inflammation. For instance, M^> efferocytosis of apoptotic cells is coupled to the generation of anti-inflammatory mediators such as IL-10 (Ricardo etal., 2008). To this effect, re-programming M^s ex vivo toward a M2 phenotype (IL-4/IL-13 stimulation) provides protection in models of renal disease, whereas the M1 phenotype (LPS stimulation) is detrimental (Wang etal., 2007). Additional research suggests that M2a and M2c phenotypes are both renoprotective, but that the latter appears to be the more effective (Wang and Harris, 2011).


Diabetic nephropathy is a chronic disease and current therapeutics primarily focus on glycemic and blood-pressure control through drugs targeting the renin-angiotensin system (RAS), such as angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). However, these treatment regimes only slow the progression of the disease, but do not halt or reverse it. Furthermore, prolonged use of RAS inhibitors may induce hyper-kalemia, reduction in systemic blood pressure and decreased renal blood flow. Therefore, there is a profound need for novel therapeutic strategies in this field and the search is ongoing (Decleves and Sharma, 2010; Shepler etal., 2012). Examples of experimental therapeutics that show potential include bardoxolone methyl, which in clinical trials increases estimated glomerular filtration rate (eGFR) and creatinine clearance, while inhibiting inflammation in diabetic patients with stage 3b-4 CKD (Pergola etal., 2011a,b; Thomas and Cooper, 2011). Pirfenidone is an oral anti-fibrotic and anti-inflammatory agent which shows therapeutic potential in DN, although it was initially developed for treatment of idiopathic pulmonary fibrosis. In a randomized, double blind study pirfenidone increased eGFR and decreased markers of inflammation (TNF, INF-y, and IL-1; Sharma etal., 2011) and has also demonstrated anti-fibrotic potential in both in vitro (Hewitson etal., 2001) and in vivo (RamachandraRao etal., 2009; Takakuta et al., 2010) models of renal disease. Vitamin D analogs, e.g., paricalcitol, may also be renoprotective agents through negatively regulating the RAS system and attenuation of renal fibrosis in rodent unilateral ureteric obstruction (UUO) models inhibiting accumulation of ECM as well as TGF-^1 and MCP-1 gene expression signaling (Li and Batuman, 2009; Li, 2010). Vitamin D analogs have also been suggested to prevent podocyte injury by promoting expression of slit diaphragm proteins (Li, 2011) and shows promising potential in emerging clinical trials reducing proteinuria in CKD patients (Li, 2010).

As inflammation is a common denominator in CKD and a hallmark of DN, pro-resolving therapeutics may have potential benefit. We recently reported that LXs are protective in CKD, as pre-treatment with LXA4 and benzo-LXA4 modulates inflammation and fibrosis in early UUO-induced injury (Borgeson etal., 2011a). UUO is an established model of progressive tubulointerstitial fibrosis and inflammation, relevant to CKD of diverse etiologies, including DN. UUO induces marked M^> infiltration, tubular cell death, fibroblast activation, and possible phenotypic transition of resident renal cells characteristic of progressive renal fibrosis (Higgins etal., 2007; Chevalier etal., 2009). Benzo-LXA and LXA4 attenuated UUO-induced fibrotic responses such as collagen accumulation by inhibiting collagen-1a2 gene expression, expression of collagen chaperone HSP47 and TGF-^1 signaling pathways (Borgeson etal., 2011a). Interestingly, RvD1 has also been demonstrated to attenuate collagen deposition in a murine model of renal ischemia reperfusion (Duffield etal., 2006). Specifically, LXs inhibited UUO-induced TGF-^1 canonical (Smad2) and non-canonical (Akt, Erk, and p38MAPK)

signaling pathways, translating to reduced pro-fibrotic signaling (Börgeson etal., 2011a). Although LXA4 did not alter the expression of TGF-ß1, it did inhibit expression of MMP2 and CTGF. This is indeed noteworthy since MMP2 activates latent TGF-ß1 and is a major driver of TGF-ß1-mediated fibrosis. The LXA4 mediated reduction of CTGF, both at mRNA and protein levels, would likely result in reduced fibrotic responses. The anti-fibrotic effect of LXs has been demonstrated in several in vitro systems, inhibiting proliferation and cell cycle progression in mesangial cells (Börgeson and Godson, 2010). Recent data also demonstrate protection by RvE and RvD in murine UUO (Qu etal., 2012). LXs also appeared to shift M^> phenotype and displayed significant pro-resolving actions in UUO-induced CKD. Whereas the total number of M^> and MCP-1 remained unaltered, LX treated animals displayed decreased pro-inflammatory IFN-y and TNF-a cytokines and increased pro-resolving IL-10 levels (Börgeson et al., 2011a). Indeed, it appeared that the LXs induced a shift the M^> phenotype toward an early stage M2c reparative phenotype, based on the high IL-10 expression induced by benzo-LXA4, although TGF-ß1 remained unaffected (Börgeson etal., 2011a).

Micro RNA (miRNA) may also prove an important therapeutic target in DN, as they have demonstrated importance in CKD pathogenesis (Kato et al., 2007; Wang et al., 2008; Long et al., 2010). We recently reported that whereas TGF-ß1 downregulates expression of the miRNA let-7c in renal epithelia, LXA4 enhances let-7c expression, and attenuates TGF-ß1 fibrotic responses as let-7c targets expression of the TGF-ßR1 (Brennan etal., in revision). Importantly, LXs inhibit ROS production (Börgeson and Godson, 2010; Börgeson etal., 2011b; Wu etal., 2012), which maybe analogous to the antioxidant effect of bardoxolone methyl (Rojas-Rivera et al., 2012). Indeed, bardoxolone methyl is an antioxidant inflammation modulator (AIM) compound, targeting Nrf2 which is a master regulator of the antioxidant response. Interestingly, LXA4 has been shown to inhibit LPS-mediated ROS production and to downregulate Nrf2 protein levels in human umbilical vein endothelial cells (HUVECs; Pang etal., 2011).


Increasing evidence supports the role of chronic inflammation in the pathogenesis of T2DM and associated complications such as DN. Pro-resolving mediators, such as LXs, resolvins, and protectins, attenuate diabetes-related pathologies, including kidney disease and adipose inflammation. Thus promoting the resolution of inflammation through use of these lipids may provide a novel therapeutic strategy in the fight against diabetes-related pathologies.


Work in Professor Godson's laboratory is supported by Science Foundation Ireland, the Health Research Board and the Government of Ireland Programme for Research in Third Level Institutions. Emma Börgeson was supported by an Embark IRCSET PhD scholarship.


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Conflict of Interest Statement: The

authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Received: 31 July 2012; accepted: 29 September 2012; published online: 18 October2012.

Citation: Borgeson E and Godson C (2012) Resolution of inflammation: therapeutic potential of pro-resolving lipids in type 2 diabetes mellitus and associated renal complications. Front. Immun. 3:318. doi: 10.3389/fimmu.2012.00318 This article was submitted to Frontiers in Inflammation, a specialty of Frontiers in Immunology.

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