YB-1: the Jekyll and Hyde of kidney disease?

Y-box-binding protein 1 is a well-described and important regulator of gene transcription, which is linked to various pathologic conditions, including inflammation and fibrosis of the kidney. The identification of a novel and protective crosstalk pathway between podocytes and tubular cells in the kidney with Y-box-binding protein 1 acting as a paracrine messenger sheds new light and provides novel opportunities for renoprotection.

Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation.

Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease. Mice with deletion of the GLP-1 receptor displayed an abnormal kidney phenotype that was accelerated by diabetes and improved with co-deletion of RAGE in vivo. Activation of the GLP-1 receptor pathway with liraglutide, an anti-diabetic treatment, downregulated kidney RAGE, reduced the expansion of bone marrow myeloid progenitors, promoted M2-like macrophage polarization and lessened markers of kidney damage in diabetic mice. Single cell transcriptomics revealed that liraglutide induced distinct transcriptional changes in kidney endothelial, proximal tubular, podocyte and macrophage cells, which were dominated by pathways involved in nutrient transport and utilization, redox sensing and the resolution of inflammation. The kidney-protective action of liraglutide was corroborated in a non-diabetic model of chronic kidney disease, the subtotal nephrectomised rat. Thus, our findings identify a novel glucose-independent kidney-protective action of GLP-1-based therapies in diabetic kidney disease and provide a valuable resource for exploring the cell-specific kidney transcriptional response ensuing from pharmacological GLP-1R agonism.

Potential of Modulating Aldosterone Signaling and Mineralocorticoid Receptor with microRNAs to Attenuate Diabetic Kidney Disease.

Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin-angiotensin-aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes.

Targeted deletion of nicotinamide adenine dinucleotide phosphate oxidase 4 from proximal tubules is dispensable for diabetic kidney disease development.

BACKGROUND: The nicotinamide adenine dinucleotide phosphate oxidase isoform 4 (Nox4) mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease (DKD) at the level of the podocyte. However, the mitochondrial localization of Nox4 and its role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in DKD within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known. METHODS: We generated a proximal tubular-specific Nox4 knockout mouse model by breeding Nox4flox/flox mice with mice expressing Cre recombinase under the control of the sodium-glucose cotransporter-2 promoter. Subsets of Nox4ptKO mice and their Nox4flox/flox littermates were injected with streptozotocin (STZ) to induce diabetes. Mice were followed for 20 weeks and renal injury was assessed. RESULTS: Genetic ablation of proximal tubular Nox4 (Nox4ptKO) resulted in no change in renal function and histology. Nox4ptKO mice and Nox4flox/flox littermates injected with STZ exhibited the hallmarks of DKD, including hyperfiltration, albuminuria, renal fibrosis and glomerulosclerosis. Surprisingly, diabetes-induced renal injury was not improved in Nox4ptKO STZ mice compared with Nox4flox/flox STZ mice. Although diabetes conferred ROS overproduction and increased the mitochondrial oxygen consumption rate, proximal tubular deletion of Nox4 did not normalize oxidative stress or mitochondrial bioenergetics. CONCLUSIONS: Taken together, these results demonstrate that genetic deletion of Nox4 from the proximal tubules does not influence DKD development, indicating that Nox4 localization within this highly energetic compartment is dispensable for chronic kidney disease pathogenesis in the setting of diabetes.

Specialized pro-resolving mediators in diabetes: novel therapeutic strategies.

Diabetes mellitus (DM) is an important metabolic disorder characterized by persistent hyperglycemia resulting from inadequate production and secretion of insulin, impaired insulin action, or a combination of both. Genetic disorders and insulin receptor disorders, environmental factors, lifestyle choices and toxins are key factors that contribute to DM. While it is often referred to as a metabolic disorder, modern lifestyle choices and nutrient excess induce a state of systemic chronic inflammation that results in the increased production and secretion of inflammatory cytokines that contribute to DM. It is chronic hyperglycemia and the low-grade chronic-inflammation that underlies the development of microvascular and macrovascular complications leading to damage in a number of tissues and organs, including eyes, vasculature, heart, nerves, and kidneys. Improvements in the management of risk factors have been beneficial, including focus on intensified glycemic control, but most current approaches only slow disease progression. Even with recent studies employing SGLT2 inhibitors demonstrating protection against cardiovascular and kidney diseases, kidney function continues to decline in people with established diabetic kidney disease (DKD). Despite the many advances and a greatly improved understanding of the pathobiology of diabetes and its complications, there remains a major unmet need for more effective therapeutics to prevent and reverse the chronic complications of diabetes. More recently, there has been growing interest in the use of specialised pro-resolving mediators (SPMs) as an exciting therapeutic strategy to target diabetes and the chronic complications of diabetes.

Lipoxins Regulate the Early Growth Response-1 Network and Reverse Diabetic Kidney Disease.

Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation.Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE-/- mice treated with streptozotocin.Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF-α, IL-1ß, NF-κB). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-ß1, PDGF, TNF-α, NF-κB) and novel (early growth response-1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF-α-driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-ß1 and TNF-αConclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.

miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7.

The cytokine transforming growth factor (TGF)-ß1 plays a central role in diabetic nephropathy (DN) with data implicating the miRNA (miR) miR-21 as a key modulator of its prosclerotic actions. In the present study, we demonstrate data indicating that miR-21 up-regulation positively correlates with the severity of fibrosis and rate of decline in renal function in human DN. Furthermore, concomitant analyses of various models of fibrotic renal disease and experimental DN, confirm tubular miR-21 up-regulation. The fibrotic changes associated with increased miR-21 levels are proposed to include the regulation of TGF-ß1-mediated mothers against decapentaplegic homolog 3 (SMAD3)- and phosphoinositide 3-kinase (PI3K)-dependent signalling pathways via co-ordinated repression of mothers against decapentaplegic homolog 7 (SMAD7) and phosphatase and tensin homologue (PTEN) respectively. This represents a previously uncharacterized interaction axis between miR-21 and PTEN-SMAD7. Targeting of these proteins by miR-21 resulted in de-repression of the respective pathways as reflected by increases in SMAD3 and V-Akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation. Many of the changes typically induced by TGF-ß1, including phosphorylation of signalling mediators, were further enhanced by miR-21. Collectively, these data present a unified model for a key role for miR-21 in the regulation of renal tubular extracellular matrix (ECM) synthesis and accumulation and provide important insights into the molecular pathways implicated in the progression of DN.

Study of microRNA in diabetic nephropathy: isolation, quantification and biological function.

In recent years, several studies have reported dysregulation of microRNA expression in disease with a growing interest focussed on targeting microRNAs as a novel therapy for human disease. This is especially true in diabetic nephropathy where the expression of several microRNAs is dysregulated, contributing to the increased expression and accumulation of extracellular matrix proteins and increased pro-fibrotic signalling, ultimately resulting in renal fibrosis. The development of various techniques and microRNA reagents has enabled work to progress very rapidly in this area. In the present article, the authors describe the methods they have used that have enabled them to contribute to our current understanding of the role of microRNAs in diabetic nephropathy.

Transforming growth factor-ß1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b.

Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-ß1 (TGF-ß1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-ß1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-ß1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-ß1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3'-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-ß1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-ß1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy.

Where are we in diabetic nephropathy: microRNAs and biomarkers?

PURPOSE OF REVIEW: Several factors are now known to contribute to the development and progression of nephropathy, particularly in diabetes. In recent times, there has been surge of interest in the role of small noncoding RNA, with several reports focusing on the effects of microRNAs on their target genes that are of relevance to nephropathy. This review focuses on recent progress in this field. RECENT FINDINGS: The list of microRNAs that have been identified to play a role in nephropathy continues to grow. Of particular interest is the fact that most microRNAs that are implicated in nephropathy are regulated by the profibrotic factor, transforming growth factor-ß. Additionally, some recent studies have used the presence of microRNAs in biofluids as a source of potential biomarkers for many diseases, particularly in diabetic nephropathy. SUMMARY: MicroRNAs hold much promise given their novelty, promiscuity and involvement in many biological and pathological processes. There are promising early signs of their potential as biomarkers as well as therapeutic targets.

microRNA in the development of diabetic complications.

Today's world population is currently faced with a new type of non-transmissible pandemic: obesity. This lifestyle-related condition is driving the emergence of the diabetes pandemic through the development of low-level chronic inflammation. In recent years, a novel class of non-coding RNA, microRNA (miRNA), have emerged as being important regulators of numerous biological functions. Among these functions are basic maintenance of cell signalling and tissue architecture. Disruption of miRNA levels can contribute not only to the development of the chronic inflammation observed in obese diabetics, but also the development of both pancreatic ß-cell dysfunction and loss, along with insulin resistance in metabolic tissues. These primary events set the scene for dysfunction of other tissues, including the retina, kidney, peripheral nerves, heart and the vasculature as a whole. Here, miRNAs again play a deterministic role in the development of a range of diseases collectively termed diabetic complications. Disturbances in miRNA levels appear to be reflected in the serum of patients and this may prove to be diagnostic in patients prior to clinical manifestation of disease, thus improving management of diabetes and its associated complications. Not only are miRNAs displaying promise as an early biomarker for disease, but a number of these miRNAs are displaying therapeutic potential with several in pre-clinical development. The present review aims to highlight our current understanding of miRNAs and their interaction with inflammatory signalling in the development and progression of diabetes and its complications. Utilization of miRNAs as biomarkers and therapeutic targets will also be considered.

Suppression of microRNA-29 expression by TGF-ß1 promotes collagen expression and renal fibrosis.

Synthesis and deposition of extracellular matrix (ECM) within the glomerulus and interstitium characterizes renal fibrosis, but the mechanisms underlying this process are incompletely understood. The profibrotic cytokine TGF-ß1 modulates the expression of certain microRNAs (miRNAs), suggesting that miRNAs may have a role in the pathogenesis of renal fibrosis. Here, we exposed proximal tubular cells, primary mesangial cells, and podocytes to TGF-ß1 to examine its effect on miRNAs and subsequent collagen synthesis. TGF-ß1 reduced expression of the miR-29a/b/c/family, which targets collagen gene expression, and increased expression of ECM proteins. In both resting and TGF-ß1-treated cells, ectopic expression of miR-29 repressed the expression of collagens I and IV at both the mRNA and protein levels by targeting the 3'untranslated region of these genes. Furthermore, we observed low levels of miR-29 in three models of renal fibrosis representing early and advanced stages of disease. Administration of the Rho-associated kinase inhibitor fasudil prevented renal fibrosis and restored expression of miR-29. Taken together, these data suggest that TGF-ß1 inhibits expression of the miR-29 family, thereby promoting expression of ECM components. Pharmacologic modulation of these miRNAs may have therapeutic potential for progressive renal fibrosis.

Ameliorating diabetes-associated atherosclerosis and diabetic nephropathy through modulation of soluble guanylate cyclase.

Diabetes mellitus (DM) is an independent risk factor for micro- and macrovascular complications such as nephropathy and atherosclerosis respectively, which are the major causes of premature morbidity and mortality in Type 1 and Type 2 diabetic patients. Endothelial dysfunction is the critical first step of vascular disease and is characterized by reduced bioavailability of the essential endothelial vasodilator, nitric oxide (NO), coupled with an elevation in inflammation and oxidative stress. A novel pathway to bolster NO activity is to upregulate soluble guanylate cyclase (sGC), an enzyme responsible for mediating the protective actions of NO. Two classes of sGC modulators exist, activators and stimulators, with differing sensitivity to oxidative stress. In this study, we investigated the therapeutic effects of the sGC stimulator BAY 41-2272 (Bay 41) and the sGC activator BAY 60-2770 (Bay 60) on endpoints of atherosclerosis and renal disease as well as inflammation and oxidative stress in diabetic Apolipoprotein E knockout (ApoE-/-) mice. We hypothesized that under oxidative conditions known to accompany diabetes, sGC activation might be more efficacious than sGC stimulation in limiting diabetic vascular complications. We demonstrate that Bay 60 not only significantly decreased nitrotyrosine staining (P < 0.01) and F4/80 positive cells by 75% (P < 0.05), but it also significantly reduced total plaque area (P < 0.05) and improved endothelial function (P < 0.01). Our data suggest an important anti-atherogenic role for Bay 60 accompanied by reduced oxidative stress and inflammation under diabetic settings. Treatment with the stimulator Bay 41, on the other hand, had minimal effects or caused no changes with respect to cardiovascular or renal pathology. In the kidneys, treatment with Bay 60 significantly lessened urinary albuminuria, mesangial expansion and nitrotyrosine staining under diabetic conditions. In summary, our head-to-head comparator is the first preclinical study to show that a sGC activator is more efficacious than a sGC stimulator for the treatment of diabetes-associated vascular and renal complications.

TGF-beta regulates miR-206 and miR-29 to control myogenic differentiation through regulation of HDAC4.

MicroRNAs (miRs) are emerging as prominent players in the regulation of many biological processes, including myogenic commitment and skeletal muscle formation. Members of the TGF-ß family can influence the proliferation and myogenic differentiation of cells, although it is presently not clear what role miRNAs play in the TGF-ß-mediated control of myogenic differentiation. Here, we demonstrate in the myogenic C2C12 cell line, and in primary muscle cells, that miR-206 and miR-29-two miRs that act on transcriptional events implicated in muscle differentiation are down-regulated by TGF-ß. We further demonstrate that TGF-ß treatment of myogenic cells is associated with increased expression of histone deacetylase 4 (HDAC4), a key inhibitor of muscle differentiation that has been identified as a target for regulation by miR-206 and miR-29. We confirmed that increased expression of miR-206 and miR-29 resulted in the translational repression of HDAC4 in the presence or absence of TGF-ß via interaction with the HDAC4 3'-untranslated region. Importantly, we found that miR-206 and miR-29 can attenuate the inhibitory actions of TGF-ß on myogenic differentiation. Furthermore, we present evidence that the mechanism by which miR-206 and miR-29 can inhibit the TGF-ß-mediated up-regulation of HDAC4 is via the inhibition of Smad3 expression, a transducer of TGF-ß signaling. These findings identify a novel mechanism of interaction between TGF-ß and miR-206 and -29 in the regulation of myogenic differentiation through HDAC4.

The role of EMT in renal fibrosis.

It is clear that the well-described phenomenon of epithelial-mesenchymal transition (EMT) plays a pivotal role in embryonic development, wound healing, tissue regeneration, organ fibrosis and cancer progression. EMTs have been classified into three subtypes based on the functional consequences and biomarker context in which they are encountered. This review will highlight findings on type II EMT as a direct contributor to the kidney myofibroblast population in the development of renal fibrosis, specifically in diabetic nephropathy, the signalling molecules and the pathways involved in type II EMT and changes in the expression of specific miRNA with the EMT process. These findings have provided new insights into the activation and development of EMT during disease processes and may lead to possible therapeutic interventions to suppress EMTs and potentially reverse organ fibrosis.

What are new avenues for renal protection, in addition to RAAS inhibition?

Diabetic nephropathy is the leading cause of endstage renal disease, with both the incidence and prevalence continuing to increase worldwide. Current treatments include optimization of glycemic and blood pressure control by targeting the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers. More innovative strategies are needed to prevent and treat this disease. New agents and approaches have recently been described that have the potential to delay the progression of diabetic kidney disease and minimize the growing burden of endstage renal disease. Possible targets include the formation of advanced glycation end products (AGEs) and the AGE receptor, increased oxidative stress and inflammation, protein kinase C, endothelin receptors, growth factors and cytokines, the vitamin D receptor, Rho-associated kinases, and the renal sympathetic system. This article reviews these recent developments as potential therapeutic interventions that may prevent this disease, with targets generally beyond the RAAS.

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function.

Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators - specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids - which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways.

Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4 Mimetics (QNX-sLXms).

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure-activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators.

Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs.

Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18-22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.

Therapeutic Potential of Lipoxin A4 in Chronic Inflammation: Focus on Cardiometabolic Disease.

Several studies have shown that failure to resolve inflammation may contribute to the progression of many chronic inflammatory disorders. It has been suggested targeting the resolution of inflammation might be a novel therapeutic approach for chronic inflammatory diseases, including inflammatory bowel disease, diabetic complications, and cardiometabolic disease. Lipoxins [LXs] are a class of endogenously generated mediators that promote the resolution of inflammation. Biological actions of LXs include inhibition of neutrophil infiltration, promotion of macrophage polarization, increase of macrophage efferocytosis, and restoration of tissue homeostasis. Recently, several studies have demonstrated that LXs and synthetic analogues protect tissues from acute and chronic inflammation. The mechanism includes down-regulation of pro-inflammatory cytokines and chemokines (e.g., interleukin-1ß and tumor necrosis factor-α), inhibition of the activation of the master pro-inflammatory pathway (e.g., nuclear factor κ-light-chain-enhancer of activated B cells pathway) and increased release of the pro-resolving cytokines (e.g., interleukin-10). Three generations of LXs analogues are well described in the literature, and more recently a fourth generation has been generated that appears to show enhanced potency. In this review, we will briefly discuss the potential therapeutic opportunity provided by lipoxin A4 as a novel approach to treat chronic inflammatory disorders, focusing on cardiometabolic disease and the current drug development in this area.