Specialized pro-resolving mediators in renal fibrosis

Molecular Aspects of Medicine xxx (2017) 1e12

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Specialized pro-resolving mediators in renal fibrosis Eoin P. Brennan*, Antonino Cacace, Catherine Godson UCD Diabetes Complications Research Centre, UCD Conway Institute & UCD School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland

a r t i c l e i n f o

a b s t r a c t

Article history: Received 28 March 2017 Received in revised form 28 April 2017 Accepted 1 May 2017 Available online xxx

Inflammation and its timely resolution play a critical role in effective host defence and wound healing. Unresolved inflammatory responses underlie the pathology of many prevalent diseases resulting in tissue fibrosis and eventual organ failure as typified by kidney, lung and liver fibrosis. The role of autocrine and paracrine mediators including cytokines, prostaglandins and leukotrienes in initiating and sustaining inflammation is well established. More recently a physiological role for specialized proresolving lipid mediators [SPMs] in modulating inflammatory responses and promoting the resolution of inflammation has been appreciated. As will be discussed in this review, SPMs not only attenuate the development of fibrosis through promoting the resolution of inflammation but may also directly suppress fibrotic responses. These findings suggest novel therapeutic paradigms to treat intractable lifelimiting diseases such as renal fibrosis. © 2017 Published by Elsevier Ltd.

Keywords: Chronic kidney disease Diabetic kidney disease Specialized pro-resolving mediators

1. Introduction Inflammation plays a critical role in host defence and tissue and wound repair. The trafficking of leukocytes to sites of injury involves integration of elaborate signals generated by proteins, peptides [chemokines and cytokines] and lipid mediators. The infiltrating cells and inflammatory signals drive the subsequent proliferative and maturation stages of the healing response, promoting regeneration and recovery (Nathan, 2002). Therefore, an essential component of effective host defence and restitution of homeostasis is effective and timely resolution of inflammation. Conventionally, the dissipation of inflammatory responses was presumed to reflect a decline in production and degradation of proinflammatory mediators including prostaglandins and leukotrienes. It is now clear that distinct mediators acting in an autocrine or paracrine fashion can promote the maintenance of homeostasis (Fullerton and Gilroy, 2016). A major advancement in our understanding of the regulators of resolution of inflammation has been made by investigation of lipid mediator biosynthesis along the continuum of inflammation and its resolution (Serhan et al., 2008). These studies have identified distinct, stereoselective pro-resolving bioactions of lipoxins (Maderna and Godson, 2009), and more recently, resolvins, protectins and maresins (Spite et al., 2014). Such

* Corresponding author. E-mail addresses: [email protected] (E.P. Brennan), [email protected] (A. Cacace), [email protected] (C. Godson).

mediators attenuate leukocyte migration, promote macrophage efferocytosis of apoptotic cells at an inflammatory focus, regulate proinflammatory gene expression and promote IL-10 production. The final processes in physiologic wound healing include fibrogenesis, characterised by the production of new extracellular matrix components to replace damaged tissue providing the scaffold for wound closure, remodeling and repair. Failure of resolution can result in persistent fibrogenesis, and collateral tissue damage includes abscess formation, scarring, fibrosis and eventual organ failure. The subversion of resolution may be reflected in many prevalent chronic diseases such as arthritis, diabetes and atherosclerosis associated with chronic, low-level ‘sterile’ inflammation, characterised by macrophage infiltration and localised cytokine/ chemokine production (Libby, 2007; Tabas and Glass, 2013). Fibrotic disorders represent a leading cause of morbidity and mortality and, with the exception of the liver, fibrosis is typically considered to be an irreversible process. Fibrotic disorders are estimated to contribute to 45% of all-cause mortality in the USA. Effective therapies are of very limited value and the majority of clinical trials have failed (Rockey et al., 2015; Thannickal et al., 2014). The mechanisms underlying the development of fibrosis are shared across multiple organs with subtle but significant differences in the relative contribution of different cell types. Renal fibrosis is the final pathological manifestation of chronic kidney disease (CKD) of diverse aetiologies reflecting an unsuccessful wound healing response to chronic, sustained injury (Duffield, 2014). An estimated 10% of the population worldwide is affected

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by CKD (Jha et al., 2013). Renal fibrosis is characterised by glomerulosclerosis, tubular atrophy and interstitial fibrosis, leading to eventual end-stage renal disease, organ failure and a requirement for renal replacement therapy (i.e. dialysis or transplantation). Diabetic kidney disease (DKD) is the leading cause of renal failure accounting for over 50% of cases of end-stage renal disease (de Boer et al., 2014). DKD reflects the convergence of inflammatory responses to the metabolic and hemodynamic stresses of diabetes in susceptible individuals (Forbes and Cooper, 2013). Current therapies for CKD rely on blockade of the renin angiotensin-aldosterone system (RAAS) (Cravedi et al., 2010; Ruggenenti et al., 2010). However, at best these interventions slow CKD progression, but cannot reverse fibrosis. Therefore, there is an urgent need to develop safe and effective therapeutics for CKD (Forbes and Cooper, 2013). However, while significant improvements in the management of risk factors for diabetic complications such as hyperlipidemia and glycemia have resulted in decreased incidence of stroke, myocardial infarction and amputation, it is noteworthy that renal complications persist, reflecting inadequate therapeutic options and increased survival (Gregg et al., 2014). Therefore, CKD and associated renal fibrosis present a major healthcare burden. Here we will review the potential of specialized pro-resolving lipid mediators [SPMs] in renal inflammation, repair and fibrosis to address this significant unmet need. 2. Specialized pro-resolving lipid mediators 2.1. Lipoxins Lipoxins (LXs) are endogenously produced eicosanoids with potent anti-inflammatory and pro-resolving effects. They were discovered in 1984 by Serhan et al when examining mixed fractions of human leukocytes and were named “lipoxins”, an acronym for lipoxygenase interaction products (Serhan et al., 1984). LipoxinA4 (LXA4: 5(S)-6(R)-15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid) and Lipoxin B4 (LXB4: 5(S)-14(R), 15(S)- trihydroxy6,8,10,12- eicosatetraenoic acid) are the principal species found in mammals. Serhan and colleagues have shown LXs are generated from the omega-6 fatty acid, arachidonic acid, in a trans-cellular manner by the sequential action of 5-lipoxygenase (5-LO) and either 12-lipoxygenase (12-LO) or 15-lipoxygenase (15-LO) (Serhan et al., 1987). LXs are produced at local sites of inflammation between neutrophils, platelets and resident tissue cells, such as epithelial cells, where they are active within the pico-to nanomolar range. It is reported that LX formation can also be induced by lowdose aspirin which, under cytokine primed conditions, can acetylate cyclooxygenase (COX)-2 and thus shift its activity from that of an endoperoxidase to a lipoxygenase (Claria and Serhan, 1995). The initial consensus that LXs are ‘made local and act local’ as conventional paracrine mediators within inflammatory exudates has recently been challenged by evidence that LXs and other SPMs can be detected in peripheral blood (Colas et al., 2014), human breast milk (Arnardottir et al., 2016), and placenta (Jones et al., 2013) at concentrations consistent with biological responses. Synthetic LX analogues resistant to enzymatic transformation have been generated and tested for their efficacy as mimetics of native LXs. 15-epi-16-(p-fluoro)-phenoxy-LXA4, [also referred to as ATLa; aspirin-triggered lipoxin analogue] has been demonstrated to preserve renal function in models of ischemic injury (Kieran et al., 2003; Leonard et al., 2002), and was protective in models of lung injury (Martins et al., 2009). A second generation of LX/ATLa analogues, resistant to b-oxidation, have also been generated through insertion of a 3-oxa group. These analogues have similar biologic activity as the 15-epi analogues and displayed efficacy on oral dosing in a model of colitis (Fiorucci et al., 2004). A third

generation of analogues features a benzo-fused ring system (O'Sullivan et al., 2007; Petasis et al., 2008). These have proven to be efficacious in promoting resolution and suppressing fibrosis in experimental models of renal and adipose inflammation as will be discussed below (Borgeson et al., 2011, 2015; Brennan et al., 2013). The original observations on the bioactions of LXs focused on their role as ‘braking signals’ in acute inflammation. This attribution reflected attenuation of prototypic inflammatory responses such as polymorphonuclear leukocyte adhesion and transmigration and eosinophil activation. Importantly, and in contrast to other antiinflammatory agents, responses to LXs do not compromise host defence (Basil and Levy, 2016; Chiang et al., 2012). Furthermore recent data show that LXA4 increases host defence and decreases pathogen virulence by inhibiting quorum sensing in Pseudomonas Aeruginosa (Wu et al., 2016). A significant advance in our understanding the continuum of effective physiologic inflammation and a restoration of homeostasis was our discovery that LXs stimulate macrophage efferocytosis of apoptotic leukocytes (Godson et al., 2000; Mitchell et al., 2002). Efferocytosis of apoptotic cells is coupled to numerous processes associated with promoting resolution. In addition to clearance of apoptotic cells pre-empting destructive cellular necrosis, efferocytosis is associated with altering macrophage activation status prompting the release of ‘anti-inflammatory’ cytokines and the biosynthesis of specialized lipid mediators (Dalli and Serhan, 2012; Maderna and Godson, 2009). The LX-mediated response of phagocytic macrophages to apoptotic polymorphonuclear leukocytes was coupled to actin cytoskeletal rearrangement (Maderna et al., 2002; Reville et al., 2006), and mediated through a specific G-protein coupled receptor (GPCR) designated ALX/FPR2 (Maderna et al., 2010). 2.2. Resolvins, protectins and maresins In studies of exudates over the course of temporally defined inflammation and its resolution, Serhan and colleagues used LCMS-MS lipidomics to detect a switch in lipid mediator biosynthesis from established proinflammatory agents typified by prostaglandins and leukotrienes to LXs and several families of novel mediators including resolvins, protectins and maresins (Serhan, 2014). Collectively these omega-6 [LXs] and omega-3 [resolvins, protectins, maresins]-derived polyunsaturated fatty acids (PUFA) metabolites are termed SPMs. The stereochemistry and organic synthesis of the SPMs has facilitated investigation of their activities in various experimental systems including animal models and isolated human leukocytes, supporting their role as immunoresolvents, re-establishing homeostasis in physiological responses. Deficits in the generation of, or response to, SPMs may be associated with several pathologies characterised by unresolved inflammation. These include atherosclerosis where plaque instability is associated with decreased levels of SPMs (Fredman et al., 2016), severe asthma (Levy et al., 2005), and increased inflammation in cystic fibrosis airways (Karp et al., 2004). Resolvins, protectins and maresins are generated from the omega-3 PUFA: eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). EPA forms E-series resolvins (RvE) by a series of enzymatic reactions involving cytochrome P450, followed by conversion to 18R-hydroxy-5Z,8Z,11Z,14Z,16E-eicosapentaenoic acid (18R-HEPE), which can be further transformed by enzymatic epoxidation and 5-LO in leukocytes to form RvEs. Endogenous DHA generates D-series resolvins (RvDs), protectins and maresins. DHA is converted into RvDs by the sequential activation of 15-LO, enzymatic epoxidation and 5-LO, where 17(S)-hydroxy Docosahexaenoic Acid (17S-HDHA) is the intermediate product. Protectins are generated from DHA via a separate pathway involving 15-LO and enzymatic epoxydation and hydrolysis where 17S-

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hydroperoxy-DHA (17S-H(p)-DHA) serves as the intermediate product. Finally, Maresin 1 (Mar1) is also produced by macrophages from endogenous DHA via 12-LO and the intermediate 14Shydro(peroxy)-DHA (14S-H(p)-DHA) (Dalli et al., 2013). As with the ATLs there are aspirin triggered epimers of the resolvins and protectins where the formation is induced by acetylated COX-2 (Chen, 2010). In experimental models of disease RvE1 was protective in periodontitis (Hasturk et al., 2006) and a murine model of colitis (Arita et al., 2005) as well as being protective against neovascularisation in retinopathy (Connor et al., 2007). RvD1 limits polymorphonuclear leukocyte infiltration in peritonitis and is protective of experimental ischemia-reperfusion induced kidney injury (Duffield et al., 2006). Protectin D1 has, similarly to the other omega-3 derived compounds, proven to be beneficial in peritonitis and kidney ischemia-reperfusion injury (Duffield et al., 2006), and also in asthma (Levy et al., 2007) and ischemic stroke (Marcheselli et al., 2003). Furthermore, diminished protectin D1 has been implicated in neural cell survival in Alzheimer's disease (Lukiw et al., 2005). Mar1 limits polymorphonuclear leukocyte infiltration in experimental acute inflammation [peritonitis] and stimulates efferocytosis of apoptotic polymorphonuclear leukocytes, pivotal processes in the resolution of inflammation. Most intriguing are observations that Mar1 accelerates surgical regeneration in the flat worm planaria, a process coupled to suppression of scarring (Serhan et al., 2012). 3. Molecular targets of SPMs ALX/FPR2 is a GPCR target of LXs and several synthetic LX mimetics, and is expressed in cells of diverse lineage and of particular relevance to inflammation and fibrosis including monocytes, macrophages, fibroblasts, epithelia, endothelia and renal mesangial cells (Maderna and Godson, 2009). ALX/FPR2 is a member of the formyl peptide receptor family comprising FPR, FPR1 and FPR2 and binds both lipid and peptide ligands including annexin-1, a glucocorticoid inducible protein released from apoptotic polymorphonuclear leukocytes that also stimulates macrophage efferocytosis of apoptotic cells (Scannell et al., 2007). Alternative ligands of ALX/FPR2 include those which elicit a pro-inflammatory response such as the acute phase protein serum amyloid A. Investigations on the duality of responses to FPR2 agonists has shown that the ALX/FPR2 dimerizes, whereby pro-resolution signals are mediated through receptor homodimers whereas proinflammatory responses are generated through ALX/FPR2-FPR heterodimers (Cooray et al., 2013). It has been proposed that epigenetic regulation of ALX/FPR2 expression could be manipulated to enhance responses to LXA4 in inflammatory disorders (Simiele et al., 2016). LXA4 can also interact with another GPCR, namely GPR32 (Krishnamoorthy et al.). LXA4 has also displayed partial antagonism of a subclass of peptide-LT receptors (CysLTs) (McMahon et al., 2000a), and acts as an allosteric modulators of CB1 receptor (Pertwee, 2012). Elaborate cross-talk between LX activated ALX/ FPR2 and other receptor classes including receptor tyrosine kinases (Baker et al., 2009; Fierro et al., 2002; McMahon et al., 2002; Mitchell et al., 2002; Rodgers et al., 2005), and serine-threonine kinases (Brennan et al., 2013) has been uncovered which underpins the role of LXs as agents that promote resolution and suppress fibrosis, as has been demonstrated in the context of kidney disease. DHA derived RvD1 binds both GPR32 and FPR2/ALX (Krishnamoorthy et al.). GPR32 was previously described as an ‘orphan’ receptor however it has been shown to bind RvD1, RvD3 and RvD5 and LXA4 in polymorphonuclear leukocytes and macrophages with high affinity. Using a GPCR screening system, RvD2 has

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been shown to bind the GPCR GPR18 (Chiang et al., 2015). EPAderived E series resolvins bind to chemerin receptor 23 (ChemR23) to stimulate macrophage phagocytosis (Arita et al., 2005), and also leukotriene B4 receptor 1 (BLT1), inhibiting calcium mobilisation and nuclear factor-kappa b (NF-kB) activation and promoting neutrophil apoptosis (El Kebir et al., 2012). At a molecular level, post-receptor targets of SPM are diverse and include attenuation of NF-kB activation, ERK activation and regulation of gene expression by transcriptional and post transcriptional mechanisms (Arita et al., 2005; Brennan et al., 2013; Kieran et al., 2003). 4. The continuum from inflammation to fibrosis - can we tell the dancer from the dance? The mechanisms underpinning execution of effective healing and restoration of physiological function are typically conserved between different organs and reflect inflammatory proliferative and resolving phases requiring inter-dependence of specific immune, mesenchymal and epithelial cell responses. Failure to effectively resolve inflammation, attenuating the classical calor, rubor, tumor dolor manifestations as described by Celsus in 100 AD can result in ’functio laesa’, fibrosis and potentially catastrophic organ failure. Fibrosis is typically associated with ‘sterile’ inflammation although it may be preceded by specific infections e.g. viral or parasitic infection in the liver, bacterial infection in the kidney. Fibrosis is a pathological process which may be considered to reflect “over-exuberant” repair and remodeling responses to inflammation or injury, including excessive deposition and insufficient resorption of extracellular matrix by myofibroblasts and loss of regenerative capacity of epithelia, rarefaction of the microvasculature and hypoxia (Manresa et al., 2014; Rockey et al., 2015). In the context of renal fibrosis two inter-related pathologies have been described which may reflect initial injury to the glomerulus [glomerulosclerosis] and tubulointerstitial fibrosis (TIF). Glomerulosclerosis reflects endothelial damage and dysfunction, proliferation and matrix production by mesangial cells, and podocyte effacement from the glomerular basement membrane. The relative contribution of mesangial cells, podocytes and parietal epithelia to matrix accumulation may depend on the particular disease. The mesangial cell is the primary source of matrix in kidney disease, whereas the podocyte is the major source of sclerotic matrix in focal segmental glomerulosclerosis and immune-mediated glomerular disease. Matrix accumulation causes diminished blood flow, hypoxia and capillary rarefaction. Tubular atrophy, interstitial fibrosis and scarring are closely associated with functional decrements (i.e. decreased glomerular filtration rate). Podocyte effacement results in exposure of the tubulointerstitum to abnormal filtrate resulting in epithelial cells generating reactive oxygen, proinflammatory cytokines and chemokines. Fibrogenic processes within the interstitium promote organ failure through disruption of tubular functions. Importantly, TIF may develop independent of glomerular injury by direct tubular injury e.g. NSAID toxicity, obstructive uropathy. 5. Cellular processes in renal fibrosis The cellular targets driving fibrotic responses have been extensively investigated and relative contributions of parenchymal and infiltrating cells as a source of matrix accumulation elucidated. The source of myofibroblasts in fibrotic tissue is highly controversial and may not be a uniform response across all organs. Activation and proliferation of alpha-smooth muscle actin expressing myofibroblasts has been proposed to represent proliferation of resident fibroblasts in response to mediators released by activated/ injured epithelia or infiltrating leukocytes such as macrophages.

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Historically, infiltration of bone marrow-derived circulating fibrocytes has been proposed together with epithelial-to-mesenchymal and endothelial-to-mesenchymal transition (Iwano et al., 2002; Kalluri and Neilson, 2003). Whether epithelia become fully differentiated to mesenchyme, analogous to tumor metastases is a vigorously debated topic in the context of renal fibrosis and fibrosis of other organs (Carew et al., 2012; LeBleu et al., 2013; Rock et al., 2011; Taura et al., 2010). Recent data propose that partial mesenchymal transition of renal tubule epithelia is an important driver of fibrosis and is associated with impaired regeneration potential (Grande et al., 2015; Lovisa et al., 2015). Contrasting data have been generated by other investigators who conclude from their intricate lineage tracing experiments in mice that pericytes associated with the microvasculature, but not epithelial cells, are the predominant myofibroblast progenitors in the kidney (Humphreys et al., 2010; Lin et al., 2008; Mack and Yanagita, 2015). Critical to pericyte detachment, motility and transition to myofibroblast are interactions between epithelia, fibroblasts, endothelia and infiltrating leukocytes in response to injury and inflammation. The response of injured epithelia further exacerbates fibrotic immune responses through the generation of paracrine mediators which may be therapeutic targets in renal fibrosis. This is evident in established in vitro models demonstrating that exposure of renal epithelia to transforming growth factor beta 1 (TGF-b1) is associated with a loss of highly specialized epithelial phenotype and up-regulation of expression of connective tissue growth factor (CTGF) and the Notch ligand Jagged-1 which can drive fibroblast activation (Brennan et al., 2012). At the epigenetic level, distinct patterns have been implicated in kidney disease development and progression. Histone acetylation has been suggested to have an important role in renal epithelialmesenchymal transition, with treatment of renal epithelial cells with trichostatin A, an inhibitor of the histone deacetylase enzyme, shown to inhibit TGF-b1 induced epithelial-mesenchymal transition (Yoshikawa et al., 2007). In renal mesangial cells, TGF-b1 can increase levels of the histone methyltransferase SET7/9, which is associated with the expression of profibrotic genes in these cells (Sun et al., 2010). Distinct methylation profiles have also been detected in fibroblasts from diseased versus healthy human kidneys, highlighting the role of epigenetics as a potential driver of myofibroblast reprogramming (Bechtel et al., 2010). In the setting of DKD, alterations in DNA methylation profiles have also been identified where the degree of methylation at distinct CpG sites correlated with time to development of DKD (Bell et al., 2010). Alterations in epigenetic chromatin marks such as histone methylation, acetylation and ubiquitination have also been identified in kidney cells in response to the high glucose environment (Gao et al., 2013; Sun et al., 2010). 6. Molecular targets in renal fibrosis Understanding the molecular mechanisms that underlie the initiation and progression of fibrosis has revealed activation of numerous common pathways, irrespective of the initiating stimulus. Strategies aimed at regressing renal fibrosis may modulate inflammation, prevent matrix deposition, promote matrix resorption, regeneration of the parenchyma and specifically target members of the TGF-b super family including TGF-b1 (Meng et al., 2016), its downstream targets and potential upstream activators, and bone morphogenetic protein agonists and antagonists (Brazil et al., 2015). TGF-b1 is the prototypic profibrotic cytokine, which stimulates the synthesis of extracellular matrix including type I and type IV collagens and fibronectin, decreases matrix degradation, and induces apoptosis of epithelia and endothelia. Acting via modulation of serine threonine kinase receptor dimers, canonical

TGF-b1 signalling involves ligand binding TGF-b receptor 2, which dimerises with TGF-b receptor 1, inducing phosphorylation of receptor activated Smad 2/3 transcription factors, heterodimerisation of Smads 2/3 with cytosolic Smad 4 and nuclear translocation. Smad 3 binds directly to promoters whereas Smad 2 and Smad 4 act as regulators of Smad 3 driven transcription. TGF-b1 stimulation thus drives expression of numerous fibrosis associated genes containing Smad responsive promoters. Increased levels of phosphorylated Smad2 and phosphorylated Smad 3 are seen in renal biopsy material from fibrotic versus healthy [control] kidneys (Dolan et al., 2005; Kim et al., 2003). TGF-b1 can also activate Smadindependent pathways. For example, MAP kinases [Erk, p38 and JNK] and Akt activation are implicated in non-canonical signalling in response to TGF-b1. TGF-b1 is produced by almost all cells and acts on pleiotropic cellular targets. In fibrosis, increased TGF-b1 may be generated by infiltrating macrophages and or by resident cells. Growth factors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) produced in response to inflammatory injury are a major stimulus for TGF-b1 production by resident renal cells such as glomerular mesangial cells. TGF-b1 is secreted in association with a latency peptide and activation may be effected in the cell matrix by integrin binding and protease activation (Annes et al., 2003). Therefore, antagonism of TGF-b1 activity may be affected by blocking circulating TGF-b1, antagonising its receptors or blocking its activation. The diverse effects on TGF-b1 as a regulator of cell proliferation and an immune modulator have engendered caution in directly targeting it for treating fibrosis, given the presumed potential for adverse events. Detailed characterisation of TGF-b1-induced responses has resulted in the identification of several other molecules which may be more appropriate targets because of their association with specific fibrotic pathways, such as CTGF (Ito et al., 1998; Murphy et al., 1999), and the bone morphogenetic protein antagonist Gremlin (McMahon et al., 2000b; Yanagita, 2005), both of which are upregulated in renal biopsies from patients with kidney fibrosis (Dolan et al., 2005; Ito et al., 1998). Notwithstanding the evidence for TGF-b1 as a target for therapeutic intervention in fibrosis, a recent clinical trial of a neutralizing humanised TGF-b1 antibody in DKD was curtailed because of lack of efficacy (Voelker et al., 2017). The degree of renal fibrosis is thought to be regulated by the turnover of extracellular matrix components, largely controlled by the matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Intriguingly, it is now apparent that not all MMPs are anti-fibrotic, and indeed some MMPs promote fibrosis. In models of kidney fibrosis, there is evidence of antifibrotic effects for MMP2, whereas MMP7 and MMP9 appears to drive kidney fibrosis (Giannandrea and Parks, 2014; Ke et al., 2017; Takamiya et al., 2013; Wang et al., 2010). While targeting the MMPs in organ fibrosis is an attractive approach, it is complicated by the fact that MMPs may affect the expression of other family members, and a specific MMP may exert pro-fibrotic effects in one organ, and anti-fibrotic in another. Future studies evaluating all relevant MMPs will be required to clarify their precise roles in renal fibrosis. Furthermore, while there is some evidence in the literature for SPM regulation of MMPs that drive endometriosis (Wu et al., 2014; Yang et al., 2015), pancreatic cancer (Zong et al., 2016), hepatocyte invasion (Zhou et al., 2009), and synoviocite activation (Sodin-Semrl et al., 2000), there is little known regarding the effects of SPMs on the MMP-TIMP axis in renal fibrosis. The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling pathway is one of the major pathways through which inflammatory signals are mediated, regulating cell proliferation and fibrosis (Brosius and He, 2015). JAK-STAT signals are initiated via extracellular ligands, including many

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cytokines, chemokines and growth factors, directing STATs to the nucleus to regulate target genes. JAK activation of STAT3 appears to play an important role in signalling from injured renal epithelia to parenchymal fibroblasts (Bienaime et al., 2016; Duffield, 2016). In the context of liver fibrosis, several studies have described the cross-talk between JAK-STAT and TGF-b1 pathways in hepatic cells via SMAD activation (Tang et al., 2017a; Yamamoto et al., 2001). Targeting this pathway in renal fibrosis has recently been the focus of significant attention, with data from early human DKD demonstrating upregulation of STAT 3 target genes in human renal biopsy material (Berthier et al., 2009), and reported efficacy of Baricitinib, a JAK/STAT inhibitor in reducing proteinuria in patients with DKD (Duffield, 2016). Inflammation is a feature of most renal pathology, and severe acute or chronic renal inflammation may lead to glomerulosclerosis, tubular atrophy, damage to renal vasculature and fibrosis (Ferenbach et al., 2007). Some kidney diseases, such as poststreptoccocal glomerulonephritis, spontaneously resolve, demonstrating the potential of endogenous repair mechanisms (Wu et al., 2009). In other types of renal disease, such as DKD, the inflammation becomes chronic and causes significant organ injury. Several large-scale studies of patients with DKD have revealed higher circulating levels of pro-inflammatory cytokines [C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule1 (ICAM-1), plasminogen activator inhibitor 1 (PAI-1) and soluble tumor necrosis factor receptors (sTNFR-1, sTNFR-2)] are associated with progression of DKD (Groop et al., 2009; Lopes-Virella et al., 2013). The key signalling pathways implicated in renal fibrosis are highlighted in Fig. 1. 7. SPMs in renal fibrosis The overwhelming experimental evidence that SPMs promote the resolution of inflammation is supportive of a role in preempting fibrotic responses. More intriguing are data directly demonstrating the capacity of SPMs to attenuate pre-existing fibrosis, the underlying mechanisms and cellular targets, as will be discussed here in the context of kidney fibrosis. LXs elicit distinct, receptor mediated responses in cellular targets of fibrosis including epithelia, fibroblasts, macrophages and glomerular mesangial cells (Maderna and Godson, 2009). LXs have been shown to promote the resolution of experimental renal injury in numerous models. For example, in experimental renal ischemia reperfusion injury we have previously demonstrated functional and morphological protection and attenuation of chemokine and cytokine responses by pre-treatment with LXs (Kieran et al., 2003; Leonard et al., 2002). Duffield and colleagues demonstrated endogenous generation of D-series resolvins and protectin D1, detectable in both kidney and plasma, 24 hours post-ischemic injury in a murine model (Duffield et al., 2006). Here, dose-dependent attenuation of ischemic injury was observed in animals pre-treated with D-series resolvins and protectin D1. These observations are consistent with effects of SPMs on PMN infiltration. Importantly, when administered 72 hours post-injury, D-series resolvins were shown to protect from fibrosis observed 15 days post-injury. Dietary Omega-3 PFUA increases endogenous renal levels of protectin D1 and 17HDHA, the latter being a metabolic marker for D-series resolvins. Interestingly, Omega-3 supplementation has been shown to attenuate inflammation, glomerulosclerosis and TIF in the remnant kidney of the 5/6 nephrectomy model of renal disease (An et al., 2009). Renal fibrosis is typically accompanied by inflammation and monocyte infiltration. Recruited macrophages acquire phenotypically distinct features consistent with roles in host defence, wound healing and immune regulation, and regeneration in response to

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the microenvironment (Mosser and Edwards, 2008). Macrophage efferocytosis of apoptotic cells is coupled to release of SPMs. LXs have been shown to re-programme cytokine-primed macrophages with a “classically activated” M1 phenotype switch to an “alternatively activated” M2 phenotypes (Mitchell et al., 2002). D-series resolvins and protectin D1 also modulate macrophage recruitment and activity, inhibiting LPS-induced TNF-a production in bone marrow derived macrophages in vitro, and furthermore reducing macrophage infiltration in an in vivo model of ischemia-reperfusion (Duffield et al., 2006). Matrix generation and accumulation in the tubulointerstitium and glomerulus can be influenced by SPMs through several mechanisms, both direct and indirect. These include attenuation of responses of mesangial cells to growth factors such as EGF and PDGF via ALX/FPR2 mediated receptor tyrosine kinase activation (McMahon et al., 2002; Rodgers et al., 2005). PDGF-induces reactive oxygen species generation in mesangial cells and this is attenuated by LXA4. Given the principle of antioxidant inflammation, modulators which attenuate reactive oxygen species and activate KeapNrf2 are potential therapeutics in DKD (Thomas, 2013), and it is interesting to speculate that such responses might also underpin the potential therapeutic benefit of LXs in DKD. Interestingly, Mar1 has been shown to attenuate inflammatory responses to high glucose including reactive oxygen species generation in cultured mouse mesangial cells (Tang et al., 2017b). Epithelial cell injury in response to TGF-b1 can perpetuate a fibrotic response through generation of soluble mediators. LXA4 attenuates TGF-b1-induced responses such as Jag-1 and CTGF expression (Brennan et al., 2013). LXA4 also inhibits TGF-b1 induced fibronectin and thrombospondin expression, key fibrotic responses. A detailed investigation of the underlying mechanism revealed distinct patterns of micro-RNA (miRNA) expression in response to TGF-b1 that were modified by LXA4. Of particular interest was LXA4-mediated upregulation of the let-7 family of miRNAs (Brennan et al., 2013). Predicted targets of let-7 include the TGFbR1, a component of the TGF-b1 receptor dimer. Indeed LX-induced upregulation of let-7 was associated with decreased expression of TGF-bR1 and an attenuation of responses to TGF-b1, including thrombospondin, Jag-1 and CTGF expression. These investigations suggested that the ability of LXs to sustain let-7 expression could reflect an important mechanism of action of LXs in maintaining renal tissue homeostasis. Importantly, our investigations also demonstrated that in biopsy tissue from humans with CKD, let-7 target genes including the prototypic fibrotic molecules collagens and thrombospondin were up regulated, reflecting decreased levels of let-7 in the kidney (Brennan et al., 2013). Let-7 delivery has subsequently been shown to suppress fibrosis in a model of kidney injury (Wang et al., 2016). In unilateral ureteric obstruction [UUO], an experimental model of renal fibrosis, we have shown that LXA4 and the synthetic LX analogue Benzo-LXA4 can modulate fibrotic responses (Borgeson et al., 2011). Here, renal gene and protein expression, collagen deposition, macrophage infiltration, and apoptosis were analyzed using manipulated kidneys from sham operations as control. These data demonstrated that LXs attenuate collagen deposition and renal apoptosis, and also shift the inflammatory milieu toward resolution, inhibiting TNF-a and IFN-g expression, while stimulating pro-resolving IL-10. LXs attenuated UUO-induced activation of MAP kinases, Akt and Smads in injured kidneys suggesting effects on both canonical and noncanonical TGF-b1 signalling. Consistent with these observations we also found that LXs directly modulated TGF-b-induced reporter gene expression, as indicated by PAI-1 luciferase activity, as well as fibroblast proliferation and Smad and MAP kinase activation. Subsequent to these investigations Qu et al., described the impact of RvE1 and D1 in renal fibrosis (Qu et al., 2012). Using the UUO model

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Fig. 1. Overview of cellular mechanisms implicated in the progression of renal fibrosis. Glomerular and tubular damage lead to altered renal morphology and function by promoting profibrotic and proinflammatory responses in renal cells. The production of growth factors by infiltrating leukocytes and resident renal cells, including transforming growth factor beta 1 (TGFb1), platelet derived growth factor (PDGF) and connective tissue growth factor (CTGF), as well as proinflammatory signals (interleukin 1 beta (IL1-b); interleukin 6 (IL-6); monocyte chemoattractant protein-1 (MCP1); nuclear factor kappa b (NF-kB); and tumor necrosis factor alpha (TNF-a)) promote renal fibrosis by recruiting, and inducing the proliferation of fibroblast-type cells, and by activation of fibroblasts to myofibroblasts and produce extracellular matrix (ECM). The principal source of renal myofibroblasts are believed to derive from resident renal fibroblasts, pericyte detachment, bone marrow derived fibroblasts, endothelial cells (endothelial-mesenchymal transition e EndoMT) and tubule epithelial cells (epithelial-mesenchymal transition e EMT). Glomerular damage can induce a proinflammatory tubular cell response via the release of cytokines, and disruption of the tubular basement membrane. Podocytes form an integral component of the glomerular filtration barrier, and sustained podocyte injury/detachment leads to progressive glomerulosclerosis.

they reported a direct effect of RvE1 in attenuating fibrosis when given before surgical obstruction and daily thereafter for the duration of the study (6 days). Here, RvE1 treatment was associated with attenuation of fibrotic responses including collagen IV deposition, a-smooth muscle actin (a-SMA) positivity (a marker of myofibroblast activation), myofibroblast production and PDGF production in the obstructed kidney. When RvD1 was given two days after injury, inhibition of fibroblast proliferation was also observed. In this model endothelial dysfunction associated with decreased eNOS3 was detected, and this was attenuated by RvD1 (Sun et al., 2013). RvD1 also suppressed Smad-3 phosphorylation in the linker region, Smad-3-JNK complex formation and Collagen I promoter activity. RvD1 has also been shown to attenuate experimental glomerulosclerosis, and daily treatment with RvD1 attenuated proteinuria, glomerulosclerosis, TIF, modified macrophage recruitment and prevented synaptopodin loss characteristic of retaining podocyte integrity (Zhang et al., 2013). Here, adriamycin-induced nephropathy increased acetylation of 14-3-3-b protein was associated with a loss of synaptopodin and this was attenuated by RvD1. In vitro studies using cultured mouse podocytes demonstrated that RvD1 prevented TNF-a-induced synaptopodin loss. The authors propose that the functional protection observed with RvD1 in Adriamycin-

treated animals reflects protection from podocyte damage. This may be of particular importance, given the functional significance of podocyte loss in numerous kidney diseases including DKD. The protective effects of RvD1 may be mediated through ALX/FPR2 which is expressed in the mouse kidneys and in podocytes and was attributed to preventing acetylation of 14-3-3-b protein thereby facilitating persistence of the degradation resistant 14-3-3-b-synaptopodin protein complex (Zhang et al., 2013). In an investigation of the effects of LXA4 and Benzo-LXA4 on obesity associated pathologies in a murine model we found that LXs altered high-fat diet [HFD; 60% fat]-induced obesity (Borgeson et al., 2015). As anticipated, obesity caused distinct pathologies including impaired glucose tolerance, adipose inflammation, fatty liver and CKD. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-a expression and M1 CD11cþ macrophages (MFs), while restoring M2 CD206þ MFs. Given the role of CD206þ macrophages in clearance of matrix debris it is tempting to speculate that this may be one of the mechanisms through which SPM can subvert fibrotic responses. We reported that LXs attenuated obesity-induced CKD; reducing glomerular expansion, mesangial matrix and urinary H2O2. LXs also attenuated liver damage as discussed below. LXs did not affect HFD-induced renal or hepatic MFs, suggesting that protection occurred via attenuation of

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adipose inflammation. Intriguingly, we have previously shown that LX upregulates expression of the suppressor of cytokine signalling (SOCS)-1 in murine ischemic renal injury (Leonard et al., 2002), and recent studies using peptidomimetics of SOCs-1 have been shown to attenuate mesangial expansion, tubular injury and fibrosis in a model of DKD. This protection was independent of changes in lipids or glycaemia (Recio et al., 2016). The cellular targets of fibrotic processes which may be modified by SPMs are highlighted in Fig. 2.

8. Imprecision medicine in renal fibrosis Current therapies for CKD and renal fibrosis lack precision and efficacy. Amongst the challenges is the lack of dynamic, predictive biomarkers. Investigating transcriptomic and genomic profiles in patients with CKD may offer insight into the variable progression rates of individual patients. Genome-wide transcriptome analysis has gained popularity as a means to acquire insight into disease pathogenesis, molecular classification, and identification of biomarkers for progression or treatment response. Advances in expression arrays and deep-sequencing technologies now make it feasible to determine transcriptome profiles at the patient level. In recent years several such studies have been performed in patients with CKD, identifying a central role for inflammation-related pathways, including the complement cascade, NF-kB and TNFa pathways (Ju et al., 2015; Schmid et al., 2006; Woroniecka et al., 2011). These studies reinforce the concept that CKD is a state of low-grade inflammation. Application of such technologies has recently been used to generate a set of genes independently predictive of renal allografts at risk of progressive injury due to fibrosis

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(O'Connell et al., 2016). Gene expression datasets can also be used to investigate drugability of target gene expression (Li et al., 2017). The underlying genetics in CKD is complex and genetic polymorphisms likely determine the individual progression rates. Genome-wide association studies (GWAS) have identified several genes which are associated with the decline of kidney function, including non-muscle myosin heavy chain type 2 isoform A (MYH9), uromodulin (UMOD), methenyltetrahydrofolate synthetase (MTHFS), eyes absent homologue 1 (EYA1), and transcription factor-7-like 2 (TCF7L2) (Kao et al., 2008; Kottgen et al., 2008, 2009). In the setting of DKD, GWAS have identified single nucleotide polymorphisms (SNPs) in AF4/FMR2 Family Member 3 (AFF3), and FERM Domain Containing 3 (FRMD3) associated with renal function decline (Bowden et al., 2004; Kao et al., 2008; Pezzolesi et al., 2009, 2010; Sandholm et al., 2012; Sandholm et al., 2017). Of particular interest, given evidence that LX modulates epidermal growth factor receptor activity (Mitchell et al., 2007), are reports of SNPs in Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4) (Sandholm et al., 2012). ErbB4 is the heterodimerisation partner of epidermal growth factor receptor and upregulation of ErbB4 increases the risk of DKD (Lee et al., 2017). Interestingly, genes which have been established as principal drivers of kidney fibrosis, such as the gene encoding for TGF-b1, have not been convincingly re-discovered in GWAS. However, while GWAS has not yet conclusively identified polymorphisms that contribute functionally to the common pathways of renal fibrosis, there is optimism that through assembly of larger patient cohorts, refinement of phenotyping to help define important subgroups for analysis, and more advanced technologies (full genome

Fig. 2. Cellular targets of SPMs in renal fibrosis. Kidney disease is typified by lesion formation due to mesangial expansion, increased extracellular matrix deposition, podocyte loss, renal tubule epithelial cell injury and polymorphonuclear (PMN) leukocyte recruitment. Key steps in renal inflammation and fibrosis which may be attenuated by SPMs are highlighted above and include leukocyte recruitment and activation [Leonard et al., 2002, Duffield et al., 2006, Godson et al., 2000 ], epithelial cytokine production and dedifferentiation [Kieran et al., 2003; Brennan et al., 2013; Duffield et al., 2006 ]; endothelial activation [Baker et al., 2009; Sun et al., 2013] fibroblast to myofibroblast activation [Qu et al., 2012; Borgeson et al., 2011]; podocyte effacement [Zhang et al., 2013], increase in macrophage M1:M2 ratio [Mitchell et al., 2002; Borgeson et al., 2011, 2015] and mesangial cell activation and matrix accumulation [(McMahon et al., 2002; Rodgers et al., 2005; Tang et al., 2017b; Wu et al., 2007; Wu et al., 2006)].

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Table 1 Protective effects of SPMs in kidney, liver and lung fibrosis. Organ SPM

Fibrosis

Kidney Lipoxins

Obesity-induced glomerulopathy Unilateral ureteral obstruction Renal ischemia reperfusion injury Resolvins Renal ischemia reperfusion injury Unilateral ureteral obstruction Adriamycin-induced nephropathy Protectins Renal ischemia reperfusion injury

Liver

Lipoxins

Obesity-induced liver hypertrophy

Lung

Lipoxins

Bleomycin-induced lung fibrosis

Effect Attenuates albuminuria, urine H2O2 and collagen deposition (Borgeson et al., 2015). Attenuates fibrosis and collagen deposition (Borgeson et al., 2011). Attenuates fibrosis, attenuates chemokine/cytokine responses (Kieran et al., 2003; Leonard et al., 2002). Attenuates renal injury and limits leukocyte infiltration (Duffield et al., 2006). RvE1/D1 Attenuates fibrosis, fibroblast proliferation and collagen deposition (Qu et al., 2012; Sun et al., 2013). RvD1 protects podocytes via 14-3-3beta acetylation (Zhang et al., 2013). Attenuates renal injury and limits leukocyte infiltration (Duffield et al., 2006).

Attenuates liver hypertrophy, triglyceride accumulation and elevated serum transaminases (Borgeson et al., 2015). Patient liver cirrhosis Altered LX biosynthesis in patients with cirrhosis (Claria et al., 1998). Resolvins Schistosoma japonicum-induced liver Attenuates inflammation, TNF-alpha production and liver fibrosis (Qiu et al., 2014). fibrosis CCl4-induced acute liver injury RvD1 attenuates liver injury involving up-regulation of HO-1 in mice (Chen et al., 2016). Obesity-induced NASH model RvD1 reduces liver macrophage infiltration and promotes M2 phenotype (Rius et al., 2014). Maresins CCl4-induced acute liver injury Attenuates liver injury via anti-oxidative effects (Li et al., 2016).

Cystic fibrosis airway epithelium Resolvins Bleomycin-induced lung fibrosis Cystic fibrosis biomarker Maresins Bleomycin-induced lung fibrosis

Blocked inflammation and fibrotic changes. Rebalance M1/M2 macrophage population (Guilherme et al., 2013; Martins et al., 2009). Repairs airway epithelia via KATP potassium channel activation (Buchanan et al., 2013; Urbach et al., 2013). RvD1 attenuates inflammation and fibrosis (Yatomi et al., 2015). Elevated RvD1 levels in CF patient plasma (Eickmeier et al., 2017). Attenuates lung fibrosis and lung epithelial injury (Wang et al., 2015).

sequencing) will reveal the genetic origins of individual susceptibilities to CKD in the future. 9. SPMs in lung and liver fibrosis Pulmonary fibrosis is a devastating, life limiting disease characterised by interstitial inflammation, fibroblast activation and ECM accumulation (Liu et al., 2017). Like CKD pulmonary fibrosis may arise from diverse causes but is a common end-stage condition. There are no curative therapies and the mean survival is 3e4 years post-diagnosis (Liu et al., 2017). SPMs have been shown to have distinct activities in the lungs (Basil and Levy, 2016). SPMs block asthma and airway hyper-responsiveness in murine models (Levy et al., 2007). In humans diminished levels of LXA4 have been recorded in sputum of patients with severe asthma and with cystic fibrosis (Karp et al., 2004). Using bleomycin-induced lung fibrosis Martins and colleagues demonstrated that pretreatment with a synthetic ATLa blocked inflammation and fibrotic changes (Martins et al., 2009). Subsequent work by these investigators demonstrated the capacity of these analogues to reverse established bleomycininduced fibrosis by a process sensitive to BOC-2, a non-selective ALX/FPR2 antagonist (Guilherme et al., 2013). ATLa treatment also attenuated bleomycin-induced TGF-b1; IL-1b, IL-17 and TNF-a release from lungs which may reflect a decrease in leukocyte infiltration and or increased efflux. Interestingly, in keeping with what we and other have observed in the kidney, the increase in M1:M2 macrophages seen in response to bleomycin was attenuated by ATLa, as was matrix accumulation (Guilherme et al., 2013). It would be interesting to know whether the altered macrophage subtypes might include fibrolytic macrophages which could phagocytose matrix accumulated in response to bleomycin treatment before intervention with ATLa. LXA4 was shown to inhibit human lung fibroblast proliferation and fibrotic gene expression [e.g. N-cadherin, a-SMA, Type I collagen, Type IV collagen] in response to TGF-b1 or to bronchoalveolar lavage fluid from acute respiratory distress syndrome patients (Zheng et al., 2016). These data closely parallel what has been reported for renal fibroblast and epithelia in the context of LX attenuation of TGF-b1einduced response (Borgeson et al., 2011; Brennan et al., 2013). Similar responses have been reported for Mar1, with pretreatment shown to inhibit TGF-b1-induced E-cadherin loss and

up regulation of a-SMA and fibronectin in cultured mouse lung epithelial cells. Under these experimental conditions Mar1 inhibited the phosphorylation of Smad 2, Smad 3 and Akt and activation of the transcription factor Snail. These in vitro observations were essentially replicated in vivo, whereby Mar1 attenuated lung fibrosis and enhanced survival in bleomycin challenged mice (Wang et al., 2015). 17 (R)-resolvin D1 has also been investigated in bleomycin-induced pulmonary fibrosis in mice and was found to attenuate inflammation, as determined by inflammatory cell infiltrate and IL-1b gene expression, and fibrosis, as measured by hydroxyproline accumulation, TGF-b1, Collagen and CTGF gene expression, when given simultaneously with bleomycin. Importantly, these responses were blocked by the antagonist BOC-PLPLP. Treatment of established fibrosis with 17 (R)-resolvin D1 also reduced fibrosis-associated with increased MMP 9 expression and improved lung function (Yatomi et al., 2015). Liver fibrosis is considered to be more reversible than that in lung or kidney. This has become apparent with the efficacy of antivirals targeting Hepatitis B and Hepatitis C, whereby inhibition of viral replication is associated with reversibility of fibrosis on follow-up biopsy (Andersson and Chung, 2009). In our investigation of the impact of LXA4 and Benzo-LXA4 on HFD-induced obesity in a model of hepatic steatosis and mild inflammation, LXs reduced adipose inflammation and attenuated liver hypertrophy, triglyceride accumulation and elevated serum transaminases (Borgeson et al., 2015). Here, LXs did not affect HFD-induced hepatic MFs. The protective effect of LXs was also seen in adiponectin knockout mice (Borgeson et al., 2015). SPM protection of adipose has been shown in ALOX5A transgenic mice by Elias and colleagues. Here, overexpression of ALOXAP in adipose was associated with increased LXA4 [and decreased LTB4] levels, mice were leaner and protected against diet induced obesity, insulin resistance, inflammation and hepatic steatosis (Elias et al., 2016). Despite equivalent calorie intake, the transgenic mice were protected from obesity and showed increased energy expenditure, with higher levels of UCP-1 detected in brown adipose tissue. The effects of upregulated LXA4 expression in the model were mimicked by the addition of exogenous LXA4 to wild type mice. Forty eight hours after a single IP injection of LXA4 increased UCP-1 and browning markers in white adipose tissue were detectable. Unfortunately, the authors do not report on either

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macro or microvascular complications in this model. RvE1 reduces Schistosoma japonicum-induced liver fibrosis in mice. Here, RvE1 was administered on the day of infection with the parasite and subsequently daily for 70 days, RvE1 treated animals had higher levels of serum IFN-g and lower levels of TNF-a than untreated infected mice. The authors concluded that the attenuation of liver fibrosis observed was secondary to reduced local inflammation (Qiu et al., 2014). In a murine model of acute liver inflammation CCl4-induced neutrophil infiltration, lipid peroxidation and pro-inflammatory cytokine production were inhibited by RvD1 which stimulated HO-1 expression and activity (Chen et al., 2016). As we have reported for LXs, RvD1 similarly skews adipose macrophages towards an M2 phenotype in HFD-induced obesity (Titos et al., 2011), and also in obese diabetic mice (Hellmann et al., 2011). Deficits in adipose SPMs have been reported in obesity in human and murine tissue, consistent with accelerated enzymatic breakdown (Claria et al., 2012). Indeed, stabilization of omega-3derived anti-inflammatory epoxides using an inhibitor of soluble epoxide hydrolase have proven beneficial in a murine model of obesity (Lopez-Vicario et al., 2015). In calorie restricted mice with nonalcoholic steatohepatitis (NASH), administration of RvD1 led to reduced hepatic macrophage infiltration and promotion of an M2 phenotype (Rius et al., 2014). The roles of SPM in renal, liver and kidney fibrosis are highlighted in Table 1. 10. Concluding remarks and future perspectives The regression of fibrosis remains a major challenge. In the context of renal disease this challenge is exacerbated by the growing burden of obesity, diabetes and associated complications such as DKD. Additional challenges include the identification of biomarkers for disease initiation, progression and potential therapeutic response. Improvements in our understanding of the basic cellular and molecular mechanisms driving inflammation and its resolution in renal disease have led to the proposal of a novel, tractable therapeutic paradigm i.e. SPM-promoted resolution. As illustrated in Fig. 2 growing evidence from in vivo models and from cellular, molecular and genetic investigations suggest that the therapeutic potential of SPMs and their synthetic mimetics may extend to the regression of renal fibrosis. Acknowledgements The authors would like to acknowledge support from Science Foundation Ireland Investigators Programme (15/IA/3152) and SFIHRB US Ireland R&D partnership (15/US/B3130). EB was supported by a Marie Curie International Fellowship. AC is supported by EVOluTION Marie Curie ITN. References An, W.S., Kim, H.J., Cho, K.H., Vaziri, N.D., 2009. Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. Am. J. physiology 297 (4), F895eF903. Andersson, K.L., Chung, R.T., 2009. Monitoring during and after antiviral therapy for hepatitis B. Hepatology 49 (5 Suppl. l), S166eS173. Annes, J.P., Munger, J.S., Rifkin, D.B., 2003. Making sense of latent TGFbeta activation. J. cell Sci. 116 (Pt 2), 217e224. Arita, M., Yoshida, M., Hong, S., Tjonahen, E., Glickman, J.N., Petasis, N.A., Blumberg, R.S., Serhan, C.N., 2005. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6trinitrobenzene sulfonic acid-induced colitis. Proc. Natl. Acad. Sci. U. S. A. 102 (21), 7671e7676. Arnardottir, H., Orr, S.K., Dalli, J., Serhan, C.N., 2016. Human milk proresolving mediators stimulate resolution of acute inflammation. Mucosal Immunol. 9 (3), 757e766. Baker, N., O'Meara, S.J., Scannell, M., Maderna, P., Godson, C., 2009. Lipoxin A4: antiinflammatory and anti-angiogenic impact on endothelial cells. J. Immunol. 182

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Brosius 3rd, F.C., He, J.C., 2015. JAK inhibition and progressive kidney disease. Curr. Opin. Nephrol. Hypertens. 24 (1), 88e95. Buchanan, P.J., McNally, P., Harvey, B.J., Urbach, V., 2013. Lipoxin A(4)-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair. American journal of physiology. Lung Cell. Mol. physiology 305 (2), L193eL201. Carew, R.M., Wang, B., Kantharidis, P., 2012. The role of EMT in renal fibrosis. Cell Tissue Res. 347 (1), 103e116. Chen, C., 2010. COX-2's new role in inflammation. Nat. Chem. Biol. 6 (6), 401e402. Chen, X., Gong, X., Jiang, R., Wang, B., Kuang, G., Li, K., Wan, J., 2016. Resolvin D1 attenuates CCl4-induced acute liver injury involving up-regulation of HO-1 in mice. Immunopharmacol. Immunotoxicol. 38 (2), 61e67. Chiang, N., Dalli, J., Colas, R.A., Serhan, C.N., 2015. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J. Exp. Med. 212 (8), 1203e1217. 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American journal of physiology. Cell physiol. 307 (1), C39eC54. Connor, K.M., SanGiovanni, J.P., Lofqvist, C., Aderman, C.M., Chen, J., Higuchi, A., Hong, S., Pravda, E.A., Majchrzak, S., Carper, D., Hellstrom, A., Kang, J.X., Chew, E.Y., Salem Jr., N., Serhan, C.N., Smith, L.E., 2007. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat. Med. 13 (7), 868e873. Cooray, S.N., Gobbetti, T., Montero-Melendez, T., McArthur, S., Thompson, D., Clark, A.J., Flower, R.J., Perretti, M., 2013. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc. Natl. Acad. Sci. U. S. A. 110 (45), 18232e18237. Cravedi, P., Ruggenenti, P., Remuzzi, G., 2010. Which antihypertensive drugs are the most nephroprotective and why? Expert Opin. Pharmacother. 11 (16), 2651e2663. Dalli, J., Serhan, C.N., 2012. Specific lipid mediator signatures of human phagocytes:

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Please cite this article in press as: Brennan, E.P., et al., Specialized pro-resolving mediators in renal fibrosis, Molecular Aspects of Medicine (2017), http://dx.doi.org/10.1016/j.mam.2017.05.001

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Catherine Godson is Professor of Molecular Medicine at University College Dublin, Ireland where she leads the Diabetes Complications Research Centre. She obtained her PhD in Pharmacology from University College Dublin and after postdoctoral fellowships at UCSD, University of Geneva and a junior faculty position at Harvard Medical School she returned to Dublin. Her investigations on the molecular mechanisms underlying the initiation, progression and potential regression of diabetic nephropathy have identified several novel therapeutic targets, susceptibility genes and potential modulators of disease.

Eoin Brennan is a Senior Research Fellow in the Diabetes Complications Research Centre at University College Dublin, Ireland. He completed his PhD at Queen's University Belfast, studying the genetic and epigenetic mechanisms of diabetic kidney disease. In 2014, he commenced a Marie Curie Fellowship at the Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne. His research interests include projects investigating micro-RNA and pro-resolution lipids as therapeutics in kidney disease. His work has identified an important role for the let7 miRNA family as potential therapeutic targets in kidney fibrosis.

Antonino Cacace is a PhD candidate in the Diabetes Complications Research Centre at University College Dublin, Ireland. His research investigating pro-resolution lipids in models of kidney disease is funded by the EVOluTION (European Vascular Intervention and Therapeutic Innovative Network) training network. He is a graduate of Pharmaceutical Chemistry and Technologies, University of Naples Frederico II.

Please cite this article in press as: Brennan, E.P., et al., Specialized pro-resolving mediators in renal fibrosis, Molecular Aspects of Medicine (2017), http://dx.doi.org/10.1016/j.mam.2017.05.001