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. 2024 May 9;17:2861–2871. doi: 10.2147/JIR.S451398

Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease

Yifang Tang 1,*, Tao Liu 2,*, Shibo Sun 3,✉, Youbo Peng 1, Xiaoxiao Huang 4, Shuangquan Wang 4, Zhu Zhou 1,✉
PMCID: PMC11090192  PMID: 38741613

Abstract

GDF-15 is an essential member of the transforming growth factor-beta superfamily. Its functions mainly involve in tissue injury, inflammation, fibrosis, regulation of appetite and weight, development of tumor, and cardiovascular disease. GDF-15 is involved in various signaling pathways, such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. In addition, several factors such as p53, ROS, and TNF-α participate the regulation of GDF-15. However, the specific mechanism of these factors regulating GDF-15 is still unclear and more research is needed to explore them. GDF-15 mainly improves the function of kidneys in CKD and plays an important role in the prediction of CKD progression and cardiovascular complications. In addition, the role of GDF-15 in the kidney may be related to the SMAD and MAPK pathways. However, the specific mechanism of these pathways remains unclear. Accordingly, more research on the specific mechanism of GDF-15 affecting kidney disease is needed in the future. In conclusion, GDF-15 may be a therapeutic target for kidney disease.

Keywords: chronic kidney disease, GDF-15, biomarker, inflammation, renal protection

Introduction

Chronic kidney disease (CKD) has garnered global attention due to its prevalence, progressive nature, and irreversibility. The renal function of patients with CKD continues to decline and leads to end-stage renal disease (ESRD) or uremia.1,2 It is estimated that CKD causes over 35.8 million disabilities and 1.2 million deaths annually.3,4 It is reported that systemic inflammation and oxidation play a central role in CKD.5–7 Diabetic kidney disease (DKD) stands as one of the most prevalent causes of CKD. Elevated oxidative stress becomes apparent when vascular or glomerular cells are exposed to high glucose levels.8 Impaired mitochondrial function can contribute to DKD.9 It is elucidated that the escalation of oxidative stress levels during the progression of CKD is a pivotal pathological characteristic. Obesity, as a risk factor for diabetes, frequently manifests in diabetes-related conditions, including DKD.10 Following prolonged obesity, inflammation and oxidative stress levels escalate within the glomeruli, leading to proteinuria.10,11 Inflammation not only accelerates CKD but also triggers complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia, and bone diseases, which significantly increase the risk of mortality.12–17 Accordingly, it is crucial to explore the relationship between oxidation and inflammatory factors and CKD to prevent CKD and its complications.

It is well known that there are numerous inflammatory factors which trigger the onset or deterioration of diseases, such as TNF-α, IL-6, IL-1β, chemokines, growth factors, and other regulatory factors.18,19 As an important inflammatory factor, growth differentiation factor 15 (GDF-15) has been the focus of increasing studies.20,21 GDF-15 is a member of transforming growth factor-beta (TGF-β) superfamily and is expressed in various tissues, such as heart, pancreas, kidney, and so on.22–24 Levels of GDF-15 expression increases under the conditions of stress or disease.25 Increasing evidence suggests that GDF-15 is associated with cardiovascular diseases, cancer, and diabetes.25–27 It is demonstrated that levels of GDF-15 are closely related to CKD and risk of cardiovascular complications in CKD.28 Moreover, the increase of GDF-15 in CKD frequently causes inflammation, oxidative stress, fibrosis, and apoptosis, which suggest that GDF-15 play an important role in CKD.29,30 In this paper, we reviewed the role and mechanism of GDF-15 in CKD.

The Structure and Functions of GDF-15

The Structure of GDF-15

GDF15 is an essential member of the TGF-β superfamily, and its gene is located on human chromosome 19 and encodes a relatively large precursor protein with two distinct domains: the precursor domain and the mature domain. Most of the precursor domain is cleavaged in cells, resulting in a biologically active C-terminal fragment which is known as the mature domain. Moreover, the mature domain not only forms a stable dimeric structure that enhances its stability in vitro but also possesses a core region composed of multiple β-folds in its three-dimensional conformation, which present similar functional properties to other members of the TGF-β superfamily. More importantly, GDF-15 undergoes various post-translational modifications such as glycosylation, phosphorylation, and lipid modification, which contribute to its increased stability and specific interactions with other biomolecules.31–34 For instance, GDF-15 binds to its receptors to exert its effects leading to specific cellular responses, such as cellular growth, differentiation, and apoptosis.26,29,35 Furthermore, GDF-15 can also block TGF-β receptors and downstream N-Myc signaling pathways, inhibiting apoptosis and collagen production in primary fibroblasts, thereby exerting anti-fibrotic effects on the kidneys.36

The Functions of GDF-15

GDF-15 is a cytokine that exhibits diverse biological functions (Figure 1). It is demonstrated that the expression of GDF-15 increases under the conditions of tissue injury, inflammation, and other pathological conditions to improve damaged tissues and further harm.37–39 It is reported that the GDF-15 inhibits cell apoptosis and consequently supports cell survival under conditions of ischemia, hypoxia, or toxic-induced damage.25,32,35 In addition, GDF-15 inhibits inflammation by reducing the infiltration of inflammatory cells, diminishing the secretion of cytokines and chemokines, and attenuating macrophage and T cell activity to suppress the release of TNF-α, IL-6, and IL-1β. Moreover, GDF-15 facilitates the transformation from these inflammatory cells to anti-inflammatory counterparts, which ultimately reduces the inflammatory response.35,40–43 Furthermore, GDF-15 plays a pivotal role in regulating appetite and weight. It is reported that increase of GDF-15 triggers a decrease in appetite by GDF-15 binding to its receptors of the hypothalamus, resulting in reduced food intake, which impacts body weight.44,45 Authors suggested that GDF-15 in the blood of obese patients presented higher concentrations, which means that a feedback regulatory mechanism responds to excessive energy intake and fat storage in GDF-15 regulating appetite and weight.27,41 Moreover, GDF-15 may contribute to the obesity-related diseases, such as diabetes and cardiovascular disease.26,46,47 Interestingly, GDF-15 demonstrates contradictory dual roles in tumor biology. On the one hand, the upregulation of GDF-15 following stress, inflammation, and tissue injury exerts a pro-apoptotic effect, countering the proliferation and survival of malignant cells.35,48 On the other hand, GDF-15 regulates the tumor microenvironment and promotes the proliferation, angiogenesis, and metastasis of tumor cells in the progression of cancers, such as breast cancer, stomach cancer, and colorectal cancer.40,49–52 In addition, studies suggest that GDF-15 increases rapidly with the occurrence of myocardial ischemia or reperfusion injury to reduce myocardial injury, inhibit inflammatory mediators such as TNF-α and IL-1β, and combat atherosclerosis and myocardial infarction.53,54 GDF-15 regulates smooth muscle cells and inhibits vascular remodeling to maintain vascular health, especially in hypertensive diseases.55,56 Moreover, GDF-15 expression is associated with reduced cardiac function, which may also represent a protective mechanism in vivo.57

Figure 1.

Figure 1

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The functions of GDF-15.

Abbreviation: GDF-15, growth differentiation factor 15.

GDF-15 and Signaling Pathways

GDF-15 binds to its receptor to trigger a series of signal cascades inside the cell, which cause a profound impact on key processes such as cell growth, migration, survival, and apoptosis. There are several signaling pathways that GDF-15 is involved in (Figure 2).

Figure 2.

Figure 2

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GDF-15 and signaling pathways.

Abbreviations: GDF-15, growth differentiation factor 15; JAK, janus kinase; STAT3, signal transduction and transcription-activating protein 3; RET, rearranged during transfection; MEK, mitogen-activated protein kinase kinase; ERK, extracellular regulated protein kinases; PIP3, phosphoinosine-triphosphate; AKT, protein kinase B; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide3-kinase; PIP2, phosphoinosine-diphosphate; ROS, reactive oxygen species; TNF-α, tumor necrosis factor α; SMAD, drosophila mothers against decapentaplegic; ALK 1–7, activin-like kinase type 1 receptors.

MAPK Pathway

The mitogen-activated protein kinase (MAPK) pathway is one of the key signal transduction pathways in cells and is widely involved in many physiological and pathological processes such as cell growth, differentiation, migration, apoptosis, and stress response. It is reported that GDF-15 activates MAPK pathways.58,59 GDF-15 activates ERK1/2, a core component of the MAPK family, by binding to its receptor to regulate various upstream kinases, such as Ras, Raf, and MEK. Activation of ERK1/2 further regulates the phosphorylation of a variety of downstream target proteins, thereby affecting cell growth, differentiation, and survival.25,60,61 GDF-15 may exert its specific effects by modulating specific branches or regulatory points of the MAPK pathway. For example, GDF-15 may promote cell survival and proliferation by enhancing the sustained activation of ERK1/2 in vascular smooth muscle cells, while GDF-15 may regulate cellular stress response and apoptosis by regulating JNK or p38 MAPK in HaCaT cells.25,62,63

PI3K/AKT Pathway

The phosphoinositide3-kinase/protein kinase B (PI3K/AKT) pathway plays a central role in cell growth, metabolism, survival, and apoptosis.64–67 PI3K is the primary promoter of PI3K/AKT pathway and is activated by various stimuli such as growth factors and insulin. Activated PI3K converts phosphoinosine-diphosphate (PIP2) to phosphoinosine-triphosphate (PIP3). As a powerful secondary messenger, PIP3 activates AKT which is also known as protein kinase B. Activated AKT subsequently inhibits the function of the pro-apoptotic protein Bcl-2 family, thereby inhibiting apoptosis.68 In addition, AKT activates mammalian target of rapamycin (mTOR) protein to stimulate cell growth and protein synthesis.69 It is reported that the GDF-15 is an important activator of the PI3K/AKT pathway. GDF-15 increases the activity of PI3K to activate AKT in certain stressful environments and pathological states, which is closely related to cell survival and proliferation. It is suggested that GDF-15 significantly reduces cardiomyocyte apoptosis in a myocardial ischemia/reperfusion injury by activating the PI3K/AKT pathway to protect the effect of the heart.70,71 In addition, GDF-15 promotes the survival, migration, and invasion of cancer cells by activating the PI3K/AKT pathway.25,35

STAT3 Pathway

The signal transduction and transcription-activating protein 3 (STAT3) pathway plays a central role in cell growth, differentiation, survival, and immune response and abnormal activation of STAT3 is implicated in various cancers, immune diseases, and inflammation-related diseases.72,73 Biologically, STAT3 is activated by a variety of signals such as growth factors, cytokines, and hormones. These stimuli first bind to their receptors to activate the janus kinase (JAK). Subsequently, JAK phosphorylates STAT3, causing it to form a dimer and transfer to the nucleus, which in turn regulates the target genes.74,75 It is reported that GDF-15 promotes the phosphorylation of STAT3 in the context of inflammation and tumor, thereby affecting cell survival, proliferation, and differentiation.76 Moreover, GDF-15 increases the survival and proliferation ability of breast tumor cells and promotes tumor progression by activating STAT3 pathway.77 In addition, the GDF-15 actives the STAT3 pathway to inhibit inflammation. It is suggested that GDF-15 inhibits the production of inflammatory factors by regulating STAT3 activity in the recruitment of inflammatory cells after myocardial infarction, which present anti-inflammatory effect of GDF-15.78

RET Pathway

Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase, which is mainly involved in the regulation of neuron growth, differentiation, and migration.79,80 GDF-15 binds to RET co-receptor to promote the activation and self-phosphorylation of RET. Activated RET further activates a variety of downstream signal molecules or pathways, such as Ras/MAPK, PI3K/AKT, or PLCγ pathways to mediate biological effects.81,82 It is reported that high expression of GDF-15 enhances RET activation in tumor cells, thereby promoting tumor cell proliferation and survival.81 In addition, GDF-15 activating RET pathway enhances cell migration and invasion in a variety of tumor models.83 Accordingly, GDF-15 is involved in the RET pathway to regulate cell growth, survival, migration, and invasion.

SMAD Pathway

Drosophila mothers against decapentaplegic (SMAD) proteins constitute a crucial class of signaling transducers, participating in the regulation of various biological processes such as cell proliferation, differentiation, and growth. The SMAD signaling pathway primarily involves transforming growth factor-β (TGF-β), bone morphogenetic protein (BMP), and activin-like kinase (ALK). It has been reported that in pressure-induced cardiac hypertrophy models, GDF-15 inhibits myocardial hypertrophy via the SMAD2/3 pathway.84 Similarly, it also reported that GDF-15 protects the heart from adrenergic-induced hypertrophy through a SMAD-independent pathway.84 GDF-15 exerts cardioprotective effects by activating ALK type 1 receptors (ALK 1–7) and phosphorylating SMAD2/3 and SMAD1/5/8. Phosphorylated SMAD proteins form heteromeric complexes with SMAD4, which are then translocated to the nucleus, activating anti-hypertrophic and anti-apoptotic pathways.30

Other Factors

Although the expression and secretion of GDF-15 is regulated by a variety of physiological and pathological conditions, the exact upstream regulatory factors and mechanisms are still being investigated. It is known that p53, ROS, and TNF-α up-regulate the expression of GDF-15.

As a well-known tumor suppressor protein, p53 is activated and stabilized with the damage of DNA. It is reported that activated p53 directly enhances the transcriptional activity of GDF-15 gene, resulting in an increase of GDF-15.85,86

Reactive oxygen species (ROS) plays a vital role in cells and is involved in many important biological processes, such as signal transduction, gene expression regulation, and cell growth.87,88 Excess ROS frequently leads to cell damage, leading to a variety of diseases, such as cancer, cardiovascular disease, neurodegenerative diseases, and premature aging.89–91 It is presented that high ROS induced by oxidative stress significantly elevates the expression and accumulation of GDF-15.92 Moreover, the upregulation of GDF-15 modulates antioxidant expression or activates antioxidant pathways to reduce the cell damage caused by ROS.48 However, persistent GDF-15 overexpression often means continuous oxidative stress, which contributes to cellular dysfunction and disease progression.

Tumor necrosis factor α (TNF-α) is a multifunctional cytokine, which plays a key role in inflammation, immune response, cell proliferation, and apoptosis.93,94 TNF-α binding to its receptor activates multiple signal transduction pathways, especially the classical NF-κB and MAPK pathways, thereby enhancing the transcriptional activity of GDF-15.30 In addition, TNF-α affects the stability of GDF-15 mRNA or interacts with microRNAs, such as miR-20a and miR-221.95,96

The Role of GDF-15 in the Kidney Diseases

Renal Protection Provided by GDF-15

The role of GDF-15 presents potential renal protective effects in kidney disease and injury, especially during inflammation, injury, and recovery.97 It is shown that the loss of GDF-15 enhances the inflammatory response, which is harmful for lipopolysaccharide-induced (LPS-induced) kidney and heart damage, while overexpression of GDF-15 improves LPS-induced organ dysfunction.98 In addition, GDF-15 is related to early renal protective injury responses by altering the behavior of immune cells, such as T cells.81 It is reported that the mice deficient in GDF-15 exhibited more severe symptoms, including increased proteinuria, crescent formation, and mesangial dilation in a model of anti-glomerular basement membrane glomerulonephritis,35 which means the critical role of GDF-15 in regulating T cells, particularly their chemotaxis within the kidney.99 In addition, GDF-15 protects the renal interstitial and tubule compartments, and deletion or absence of this GDF-15 gene results in increased damage of tubule and interstitial in diabetes, though the glomerular damage is not impaired.26,100 Moreover, renal injury causes a notable upregulation of GDF-15 at the proximal renal tubule site, which induces up-expression of Klotho protein to improve kidney injury.101 Accordingly, GDF-15 presents the renal protection.

Chronic Kidney Disease

CKD is a global health issue due to its association with multiple complications and adverse outcomes.102 In recent years, the research mainly focuses on the predictive value of GDF-15 for the progression of CKD, especially for diabetic nephropathy. In addition, another focus is the role of GDF-15 in the occurrence of complications of CKD, such as cardiovascular risk, renal fibrosis, mineral bone disease, and anemia.

Meanwhile, elevation of GDF-15 is related to adverse outcomes of kidney disease, which suggest GDF-15 may be an early warning biomarker for CKD.103 It is reported that circulating levels of GDF-15 are correlated with renal expression of GDF-15, which is significantly associated with the risk of CKD progression,29 which suggests that circulating GDF-15 can independently predict CKD progression and poor prognosis.98 Moreover, high levels of GDF-15 are significantly associated with increased all-cause and cardiovascular mortality and morbidity in patients with diabetic kidney disease. Notably, this association appears to reflect a more rapid deterioration of renal function than being directly related to the development of ESRD.104 Accordingly, GDF-15 may play an important role in early prediction of kidney function decline. In addition, it is confirmed that high circulating levels of GDF-15 are associated with type 2 diabetic nephropathy, which means GDF-15 may be a potential biomarker for type 2 diabetic nephropathy.105 It is reported that the GDF-15 is an important activator of the PI3K/AKT pathway. The PI3K/AKT signaling pathway attenuates cellular apoptosis in CKD. Glucagon-like peptide-1 (GLP-1) receptor agonists, commonly utilized as fundamental therapeutic agents in CKD,106 inhibit protein kinase C (PKC)β activation,107 promote insulin/IRS1 signaling, and via the PI3K/Akt pathway, mediate increased production of nitric oxide (NO), inducing vasodilation and inhibiting podocyte apoptosis.108 Consequently, GDF-15 can suppress CKD cellular apoptosis via the PI3K/AKT signaling pathway, exerting renal protective effects.

GDF-15 is also involved in the occurrence of complications in CKD.109–111 It is reported that GDF-15 is independently associated with cardiovascular risk in patients with diabetic nephropathy.104 GDF-15 is more closely associated with microvascular complications, especially diabetic nephropathy, than with macrovascular complications.81 In addition, GDF-15 is more closely associated with heart failure, especially heart failure with preserved ejection fraction in CKD.112,113 Moreover, GDF-15 is related with the complications such as renal fibrosis.29 It is suggested that GDF-15 plays a role in the development of mineral bone disorders due to its association with vitamin D synthesis and phosphorus metabolism.114 Additionally, elevated levels of GDF-15 are correlated with reduced erythropoiesis and impaired iron utilization, which may lead to anemia in CKD.115,116

Kidney Transplantation

GDF-15 plays an important role in post-transplant outcomes. The prevalence of anemia among kidney transplant recipients is notably high, primarily attributed to long-term uremia or the nephrotoxicity of immunosuppressive drugs.117 It is suggested that there is a plausible link between GDF-15 and anemia in patients with kidney transplantation. Intriguingly, GDF-15 levels reduce in kidney transplantation, while increases in single nephrectomy.118 It seems that elevated levels of GDF-15 may reflect the presence of chronic kidney disease rather than being solely attributable to transplantation itself. Notably, there is an intriguing correlation between GDF-15 and mortality following kidney transplantation,119 which suggest that GDF-15 may be a predictive indicator for early mortality after surgery. Remarkably, this predictive power even enhances the accuracy of the EPTS score which is a scoring model used to assess expected post-transplant survival among candidates for kidney transplantation.119 Apart from its prognostic value regarding mortality rates, GDF-15 also serves as a key predictor for cardiovascular events.118

Conclusions and Prospects

GDF-15 plays a crucial role in tissue injury, inflammation, fibrosis, regulation of appetite and weight, tumor development, cardiovascular disease, and other biological functions following the processes of glycosylation and phosphorylation. GDF-15 is involved in various signaling pathways such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. In addition, GDF-15 is regulated by several factors such as p53, ROS, and TNF-α. In CKD, GDF-15 are strongly associated with CKD survival rate, disease progression rate, cardiovascular complications risk, and complications such as renal fibrosis and anemia. Particularly, GDF-15 are linked to both decreased kidney function and higher risk for cardiovascular diseases in diabetic nephropathy patients. Moreover, GDF-15 has shown potential value in predicting post-transplantation outcomes, such as anemia occurrence, cardiovascular events, and mortality rates. However, the specific mechanism that GDF-15 affects kidneys remains unclear. In addition, more research is needed to explore the role of GDF-15 in common CKD, such as IgA nephropathy, membranous nephropathy, and lupus nephritis. In conclusion, GDF-15 may be a therapeutic target.

Funding Statement

This work was supported by Yunnan Major Scientific and Technological Project, (grant no. 202102AA100060), Yunnan Revitalization Talent Support Program, the National Natural Science Foundation of China (grant no. 82160007), the Yunnan Provincial Science and Technology Department (grant no. 2019FE001(−58), 202201AY070001(−074)), Yunnan Province young and middle-aged academic and technical leaders reserve talent project (grant no. 202305AC160017), 535 Talent Project of First Affiliated Hospital of Kunming Medical University (grant no. 2023535D12), and Student Innovation Fund project of Kunming Medical University (grant no.2022JXD212, 2022JXD227).

Disclosure

The authors report no conflicts of interest in this work.

References

  • 1.Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Suppl. 2022;12(1):7–11. doi: 10.1016/j.kisu.2021.11.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Kalantar-Zadeh K, Jafar TH, Nitsch D, Neuen BL, Perkovic V. Chronic kidney disease. Lancet. 2021;398:786–802. [DOI] [PubMed] [Google Scholar]
  • 3.Mrug M, Bloom MS, Seto C, et al. Genetic testing for chronic kidney diseases: clinical utility and barriers perceived by nephrologists. Kidney Med. 2021;3(6):1050–1056. doi: 10.1016/j.xkme.2021.08.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Jdiaa SS, Mansour R, El Alayli A, Gautam A, Thomas P, Mustafa RA. COVID-19 and chronic kidney disease: an updated overview of reviews. J Nephrol. 2022;35(1):69–85. doi: 10.1007/s40620-021-01206-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Bikbov B, Purcell CA, Levey AS. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709–733. doi: 10.1016/S0140-6736(20)30045-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Irazabal MV, Torres VE. Reactive oxygen species and redox signaling in chronic kidney disease. Cells. 2020;9(6):1342. doi: 10.3390/cells9061342 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Tirichen H, Yaigoub H, Xu W, Wu C, Li R, Li Y. Mitochondrial reactive oxygen species and their contribution in chronic kidney disease progression through oxidative stress. Front Physiol. 2021;12:627837. doi: 10.3389/fphys.2021.627837 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Inoguchi T, Sonta T, Tsubouchi H, et al. Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase. J Am Soc Nephrol. 2003;14(suppl_3):S227–232. doi: 10.1097/01.ASN.0000077407.90309.65 [DOI] [PubMed] [Google Scholar]
  • 9.Mima A. Mitochondria-targeted drugs for diabetic kidney disease. Heliyon. 2022;8(2):e08878. doi: 10.1016/j.heliyon.2022.e08878 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Mima A. Inflammation and oxidative stress in diabetic nephropathy: new insights on its inhibition as new therapeutic targets. J Diabetes Res. 2013;2013:248563. doi: 10.1155/2013/248563 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Mima A, Yasuzawa T, King GL, Ueshima S. Obesity-associated glomerular inflammation increases albuminuria without renal histological changes. FEBS Open Bio. 2018;8(4):664–670. doi: 10.1002/2211-5463.12400 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Graterol Torres F, Molina M, Soler-Majoral J, et al. Evolving concepts on inflammatory biomarkers and malnutrition in chronic kidney disease. Nutrients. 2022;15(1):14. doi: 10.3390/nu15010014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Valdivielso JM, Rodríguez-Puyol D, Pascual J, et al. Atherosclerosis in chronic kidney disease: more, less, or just different? Arterioscler. Thromb Vasc Biol. 2019;39(10):1938–1966. doi: 10.1161/ATVBAHA.119.312705 [DOI] [PubMed] [Google Scholar]
  • 14.Wang XR, Zhang JJ, Xu XX, Wu YG. Prevalence of coronary artery calcification and its association with mortality, cardiovascular events in patients with chronic kidney disease: a systematic review and meta-analysis. Ren Fail. 2019;41(1):244–256. doi: 10.1080/0886022X.2019.1595646 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.van de Wouw J, Broekhuizen M, Sorop O, et al. Chronic kidney disease as a risk factor for heart failure with preserved ejection fraction: a focus on microcirculatory factors and therapeutic targets. Front Physiol. 2019;10:1108. doi: 10.3389/fphys.2019.01108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Hanna RM, Streja E, Kalantar-Zadeh K. Burden of anemia in chronic kidney disease: beyond erythropoietin. Adv Ther. 2021;38(1):52–75. doi: 10.1007/s12325-020-01524-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Cannata-Andía JB, Martín-Carro B, Martín-Vírgala J, et al. Chronic kidney disease-mineral and bone disorders: pathogenesis and management. Calcif Tissue Int. 2021;108(4):410–422. doi: 10.1007/s00223-020-00777-1 [DOI] [PubMed] [Google Scholar]
  • 18.Ghassib I, Chen Z, Zhu J, Wang HL. Use of IL-1 β, IL-6, TNF-α, and MMP-8 biomarkers to distinguish peri-implant diseases: a systematic review and meta-analysis. Clin Implant Dent Relat Res. 2019;21(1):190–207. doi: 10.1111/cid.12694 [DOI] [PubMed] [Google Scholar]
  • 19.Hammad AM, Ibrahim YA, Khdair SI, et al. Metformin reduces oxandrolone- induced depression-like behavior in rats via modulating the expression of IL-1β, IL-6, IL-10 and TNF-α. Behav Brain Res. 2021;414:113475. doi: 10.1016/j.bbr.2021.113475 [DOI] [PubMed] [Google Scholar]
  • 20.Bermúdez B, López S, Pacheco YM, et al. Influence of postprandial triglyceride-rich lipoproteins on lipid-mediated gene expression in smooth muscle cells of the human coronary artery. Cardiovasc Res. 2008;79(2):294–303. doi: 10.1093/cvr/cvn082 [DOI] [PubMed] [Google Scholar]
  • 21.Ding Q, Mracek T, Gonzalez-Muniesa P, et al. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes. Endocrinology. 2009;150(4):1688–1696. doi: 10.1210/en.2008-0952 [DOI] [PubMed] [Google Scholar]
  • 22.Yokoyama-Kobayashi M, Saeki M, Sekine S, Kato S. Human cDNA encoding a novel TGF-beta superfamily protein highly expressed in placenta. J Biochem. 1997;122(3):622–626. doi: 10.1093/oxfordjournals.jbchem.a021798 [DOI] [PubMed] [Google Scholar]
  • 23.Koopmann J, Buckhaults P, Brown DA, et al. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res. 2004;10(7):2386–2392. doi: 10.1158/1078-0432.CCR-03-0165 [DOI] [PubMed] [Google Scholar]
  • 24.Tan M, Wang Y, Guan K, Sun Y. PTGF-β, a type β transforming growth factor (TGF-β) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-β signaling pathway. Proc Natl Acad Sci U S A. 2000;97(1):109–114. doi: 10.1073/pnas.97.1.109 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Fang L, Li F, Gu C. GDF-15: a multifunctional modulator and potential therapeutic target in cancer. Curr Pharm Des. 2019;25(6):654–662. doi: 10.2174/1381612825666190402101143 [DOI] [PubMed] [Google Scholar]
  • 26.Xiao QA, He Q, Zeng J, Xia X. GDF-15, a future therapeutic target of glucolipid metabolic disorders and cardiovascular disease. Biomed Pharmacother. 2022;146:112582. doi: 10.1016/j.biopha.2021.112582 [DOI] [PubMed] [Google Scholar]
  • 27.Ouyang J, Isnard S, Lin J, et al. GDF-15 as a weight watcher for diabetic and non-diabetic people treated with metformin. Front Endocrinol. 2020;11:581839. doi: 10.3389/fendo.2020.581839 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Benes J, Kotrc M, Wohlfahrt P, et al. The Role of GDF-15 in heart failure patients with chronic kidney disease. Can J Cardiol. 2019;35(4):462–470. doi: 10.1016/j.cjca.2018.12.027 [DOI] [PubMed] [Google Scholar]
  • 29.Tuegel C, Katz R, Alam M, et al. GDF-15, galectin 3, soluble ST2, and risk of mortality and cardiovascular events in CKD. Am J Kidney Dis. 2018;72(4):519–528. doi: 10.1053/j.ajkd.2018.03.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Adela R, Banerjee SK. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res. 2015;2015:490842. doi: 10.1155/2015/490842 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Zhao Z, Zhang J, Yin L, et al. Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL. Aging. 2020;12(22):22564–22581. doi: 10.18632/aging.103830 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Verhamme FM, Freeman CM, Brusselle GG, Bracke KR, Curtis JL. GDF-15 in pulmonary and critical care medicine. Am J Respir Cell Mol Biol. 2019;60(6):621–628. doi: 10.1165/rcmb.2018-0379TR [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Desmedt S, Desmedt V, De Vos L, Delanghe JR, Speeckaert R, Speeckaert MM. Growth differentiation factor 15: a novel biomarker with high clinical potential. Crit Rev Clin Lab Sci. 2019;56(5):333–350. doi: 10.1080/10408363.2019.1615034 [DOI] [PubMed] [Google Scholar]
  • 34.Sithiravel C, Røysland R, Alaour B, et al. Biological variation, reference change values and index of individuality of GDF-15. Clin Chem Lab Med. 2022;60(4):593–596. doi: 10.1515/cclm-2021-0769 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Wischhusen J, Melero I, Fridman WH. Growth/differentiation factor-15 (GDF-15): from biomarker to novel targetable immune checkpoint. Front Immunol. 2020;11:951. doi: 10.3389/fimmu.2020.00951 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Kim YI, Shin HW, Chun YS, Park JW. CST3 and GDF15 ameliorate renal fibrosis by inhibiting fibroblast growth and activation. Biochem Biophys Res Commun. 2018;500(2):288–295. doi: 10.1016/j.bbrc.2018.04.061 [DOI] [PubMed] [Google Scholar]
  • 37.Ahmed DS, Isnard S, Berini C, Lin J, Routy JP, Royston L. Coping with stress: the mitokine GDF-15 as a biomarker of COVID-19 severity. Front Immunol. 2022;13:820350. doi: 10.3389/fimmu.2022.820350 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Mastrobattista E, Lenze EJ, Reynolds CF, et al. Late-life depression is associated with increased levels of GDF-15, a pro-aging mitokine. Am J Geriatr Psychiatry. 2023;31(1):1–9. doi: 10.1016/j.jagp.2022.08.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Yang M, Darwish T, Larraufie P, et al. Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells. Sci Rep. 2021;11(1):2529. doi: 10.1038/s41598-021-81349-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Lodi RS, Yu B, Xia L, Liu F. Roles and regulation of growth differentiation factor-15 in the immune and tumor microenvironment. Hum Immunol. 2021;82(12):937–944. doi: 10.1016/j.humimm.2021.06.007 [DOI] [PubMed] [Google Scholar]
  • 41.Schwarz A, Kinscherf R, Bonaterra GA. Role of the stress- and inflammation-induced cytokine GDF-15 in cardiovascular diseases: from basic research to clinical relevance. RCM. 2023;2:24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Roth P, Junker M, Tritschler I, et al. GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin Cancer Res. 2010;16(15):3851–3859. doi: 10.1158/1078-0432.CCR-10-0705 [DOI] [PubMed] [Google Scholar]
  • 43.Chen J, Luo F, Fang Z, Zhang W. GDF-15 levels and atherosclerosis. Int J Cardiol. 2018;257:36. doi: 10.1016/j.ijcard.2017.10.037 [DOI] [PubMed] [Google Scholar]
  • 44.Blanco AM, Bertucci JI, Velasco C, Unniappan S. Growth differentiation factor 15 (GDF-15) is a novel orexigen in fish. Mol Cell Endocrinol. 2020;505:110720. doi: 10.1016/j.mce.2020.110720 [DOI] [PubMed] [Google Scholar]
  • 45.Molfino A, Amabile MI, Imbimbo G, et al. Association between growth differentiation factor-15 (GDF-15) serum levels, anorexia and low muscle mass among cancer patients. Cancers. 2020;13(1):13. doi: 10.3390/cancers13010013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Valenzuela-Vallejo L, Chrysafi P, Bello-Ramos J, Bsata S, Mantzoros CS. Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity. Metabolism. 2022;133:155237. doi: 10.1016/j.metabol.2022.155237 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Merchant RA, Chan YH, Duque G, Bencivenga L. GDF-15 is associated with poor physical function in prefrail older adults with diabetes. J Diabetes Res. 2023;2023:2519128. doi: 10.1155/2023/2519128 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Verhamme FM, Seys LJM, De Smet EG, et al. Elevated GDF-15 contributes to pulmonary inflammation upon cigarette smoke exposure. Mucosal Immunol. 2017;10(6):1400–1411. doi: 10.1038/mi.2017.3 [DOI] [PubMed] [Google Scholar]
  • 49.Mielcarska S, Stopińska K, Dawidowicz M, et al. GDF-15 level correlates with CMKLR1 and VEGF-A in tumor-free margin in colorectal cancer. Curr Med Sci. 2021;41(3):522–528. doi: 10.1007/s11596-021-2335-0 [DOI] [PubMed] [Google Scholar]
  • 50.Hasanpour Segherlou Z, Nouri-Vaskeh M, Noroozi Guilandehi S, et al. GDF-15: diagnostic, prognostic, and therapeutic significance in glioblastoma multiforme. J Cell Physiol. 2021;236(8):5564–5581. doi: 10.1002/jcp.30289 [DOI] [PubMed] [Google Scholar]
  • 51.Zhang H, Zhou Y, Cui B, Liu Z, Shen H. Novel insights into astrocyte-mediated signaling of proliferation, invasion and tumor immune microenvironment in glioblastoma. Biomed Pharmacother. 2020;126:110086. doi: 10.1016/j.biopha.2020.110086 [DOI] [PubMed] [Google Scholar]
  • 52.Haake M, Haack B, Schäfer T, et al. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun. 2023;14(1):4253. doi: 10.1038/s41467-023-39817-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Preusch MR, Baeuerle M, Albrecht C, et al. GDF-15 protects from macrophage accumulation in a mousemodel of advanced atherosclerosis. Eur J Med Res. 2013;18(1):19. doi: 10.1186/2047-783X-18-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Maimaiti Y, Cheng H, Guo Z, Yu X, Tuohuti A, Li G. Correlation between serum GDF-15 level and pulmonary vascular morphological changes and prognosis in patients with pulmonary arterial hypertension. Front Cardiovasc Med. 2023;10:1085122. doi: 10.3389/fcvm.2023.1085122 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.May BM, Pimentel M, Zimerman LI, Rohde LE. GDF-15 as a Biomarker in Cardiovascular Disease. Arq Bras Cardiol. 2021;116(3):494–500. doi: 10.36660/abc.20200426 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Bonaterra GA, Struck N, Zuegel S, et al. Characterization of atherosclerotic plaques in blood vessels with low oxygenated blood and blood pressure (Pulmonary trunk): role of growth differentiation factor-15 (GDF-15). BMC Cardiovasc Disord. 2021;21(1):601. doi: 10.1186/s12872-021-02420-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Bettencourt P, Ferreira-Coimbra J, Rodrigues P, et al. Towards a multi-marker prognostic strategy in acute heart failure: a role for GDF-15. ESC Heart Fail. 2018;5(6):1017–1022. doi: 10.1002/ehf2.12301 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Braicu C, Buse M, Busuioc C, et al. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers. 2019;12(1):11. doi: 10.3390/cancers12010011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Lee S, Rauch J, Kolch W. Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity. Int J Mol Sci. 2020;17(1):21. doi: 10.7150/ijms.39074 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Sun Y, Lin J, Zhao T, Zhang L. GDF-15 promotes proliferation of vascular smooth muscle cells through MAPK-activated protein kinase pathways. Int J Clin Exp Med. 2019;12:10093–10100. [Google Scholar]
  • 61.Wang SF, Chen S, Tseng LM, Lee HC. Role of the mitochondrial stress response in human cancer progression. Exp Biol Med. 2020;245(10):861–878. doi: 10.1177/1535370220920558 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Dong G, Zheng QD, Ma M, et al. Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15. Cancer Med. 2018;7(3):820–830. doi: 10.1002/cam4.1330 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Decean HP, Brie IC, Tatomir CB, Perde-Schrepler M, Fischer-Fodor E, Virag P. Targeting MAPK (p38, ERK, JNK) and inflammatory CK (GDF-15, GM-CSF) in UVB-activated human skin cells with Vitis vinifera seed extract. J Environ Pathol Toxicol Oncol. 2018;37(3):261–272. doi: 10.1615/JEnvironPatholToxicolOncol.2018027009 [DOI] [PubMed] [Google Scholar]
  • 64.Jafari M, Ghadami E, Dadkhah T, Akhavan-Niaki H. PI3k/AKT signaling pathway: erythropoiesis and beyond. J Cell Physiol. 2019;234(3):2373–2385. doi: 10.1002/jcp.27262 [DOI] [PubMed] [Google Scholar]
  • 65.Very N, Vercoutter-Edouart AS, Lefebvre T, Hardivillé S, El Yazidi-Belkoura I. Cross-dysregulation of O-GlcNAcylation and PI3K/AKT/mTOR axis in human chronic diseases. Front Endocrinol. 2018;9:602. doi: 10.3389/fendo.2018.00602 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Nur Husna SM, Tan HT, Mohamud R, Dyhl-Polk A, Wong KK. Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review. Ther Adv Med Oncol. 2018;10:1758835918808509. doi: 10.1177/1758835918808509 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Matsuda S, Ikeda Y, Murakami M, Nakagawa Y, Tsuji A, Kitagishi Y, Roles of PI3K/AKT/GSK3 Pathway Involved in Psychiatric Illnesses. Diseases. 2019;1:7. doi: 10.3390/diseases7010022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Li L, Wang F, Zhang J, et al. Typical phthalic acid esters induce apoptosis by regulating the PI3K/Akt/Bcl-2 signaling pathway in rat insulinoma cells. Ecotoxicol Environ Saf. 2021;208:111461. doi: 10.1016/j.ecoenv.2020.111461 [DOI] [PubMed] [Google Scholar]
  • 69.Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019;59:125–132. doi: 10.1016/j.semcancer.2019.07.009 [DOI] [PubMed] [Google Scholar]
  • 70.Arkoumani M, Papadopoulou-Marketou N, Nicolaides NC, Kanaka-Gantenbein C, Tentolouris N, Papassotiriou I. The clinical impact of growth differentiation factor-15 in heart disease: a 2019 update. Crit Rev Clin Lab Sci. 2020;57(2):114–125. doi: 10.1080/10408363.2019.1678565 [DOI] [PubMed] [Google Scholar]
  • 71.Xiangrui Q, Junhui L, Rui H, Xiaozhen Z. GDF-15 in plasma and circulating mononuclear cells and NT-proBNP for diagnosis of chronic heart failure and predicting cardiovascular disease events. Nan Fang Yi Ke Da Xue Xue Bao. 2019;39:1273–1279. doi: 10.12122/j.issn.1673-4254.2019.11.02 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X. Targeting STAT3 in cancer immunotherapy. Mol Cancer. 2020;19(1):145. doi: 10.1186/s12943-020-01258-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Wang HQ, Man QW, Huo FY, et al. STAT3 pathway in cancers: past, present, and future. MedComm. 2022;3(2):e124. doi: 10.1002/mco2.124 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Jin W. Role of JAK/STAT3 signaling in the regulation of metastasis, the transition of cancer stem cells, and chemoresistance of cancer by epithelial-mesenchymal transition. Cells. 2020;9(1):217. doi: 10.3390/cells9010217 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Wang T, Fahrmann JF, Lee H, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 2018;27(1):136–150.e135. doi: 10.1016/j.cmet.2017.11.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Park JY, Yoo KD, Shin SJ, Kim KS, Kim YS, Yang SH. FP260Inhibition of CXCR3 expression through blockade of STAT3 alpha signaling down-regulate inflammation of renal ischemia-reperfusion injury. Nephrol Dial Transplant. 2019;34(Supplement_1). doi: 10.1093/ndt/gfz106.FP260 [DOI] [Google Scholar]
  • 77.Blanchette-Farra N, Kita D, Konstorum A, et al. Contribution of three-dimensional architecture and tumor-associated fibroblasts to hepcidin regulation in breast cancer. Oncogene. 2018;37(29):4013–4032. doi: 10.1038/s41388-018-0243-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Kempf T, Zarbock A, Widera C, et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med. 2011;17(5):581–588. doi: 10.1038/nm.2354 [DOI] [PubMed] [Google Scholar]
  • 79.Enomoto H, Crawford PA, Gorodinsky A, Heuckeroth RO, Johnson EM, Milbrandt J. RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development. 2001;128(20):3963–3974. doi: 10.1242/dev.128.20.3963 [DOI] [PubMed] [Google Scholar]
  • 80.Enomoto H, Heuckeroth RO, Golden JP, Johnson EM, Milbrandt J. Development of cranial parasympathetic ganglia requires sequential actions of GDNF and neurturin. Development. 2000;127(22):4877–4889. doi: 10.1242/dev.127.22.4877 [DOI] [PubMed] [Google Scholar]
  • 81.Iglesias P, Silvestre RA, Díez JJ. Growth differentiation factor 15 (GDF-15) in endocrinology. Endocrine. 2023;81(3):419–431. doi: 10.1007/s12020-023-03377-9 [DOI] [PubMed] [Google Scholar]
  • 82.Bou Antoun N, Chioni AM. Dysregulated signalling pathways driving anticancer drug resistance. Int J Mol Sci. 2023;25(1):24. doi: 10.3390/ijms25010024 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Muniyan S, Pothuraju R, Seshacharyulu P, Batra SK. Macrophage inhibitory cytokine-1 in cancer: beyond the cellular phenotype. Cancer Lett. 2022;536:215664. doi: 10.1016/j.canlet.2022.215664 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Xu J, Kimball TR, Lorenz JN, et al. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circul Res. 2006;98(3):342–350. doi: 10.1161/01.RES.0000202804.84885.d0 [DOI] [PubMed] [Google Scholar]
  • 85.Heduschke A, Ackermann K, Wilhelm B, et al. GDF-15 deficiency reduces autophagic activity in human macrophages in vitro and decreases p62-accumulation in atherosclerotic lesions in mice. Cells. 2021;11(1):10. doi: 10.3390/cells11010010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Ranjbaran R, Abbasi M, Rahimian E, et al. GDF-15 negatively regulates excess erythropoiesis and its overexpression is involved in erythroid hyperplasia. Exp Cell Res. 2020;397(2):112346. doi: 10.1016/j.yexcr.2020.112346 [DOI] [PubMed] [Google Scholar]
  • 87.Perillo B, Di Donato M, Pezone A, et al. ROS in cancer therapy: the bright side of the moon. Exp Mol Med. 2020;52(2):192–203. doi: 10.1038/s12276-020-0384-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Nakamura H, Takada K. Reactive oxygen species in cancer: current findings and future directions. Cancer Sci. 2021;112:3945–3952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Madreiter-Sokolowski CT, Thomas C, Ristow M. Interrelation between ROS and Ca(2+) in aging and age-related diseases. Redox Biol. 2020;36:101678. doi: 10.1016/j.redox.2020.101678 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Hajam YA, Rani R, Ganie SY, et al. Oxidative stress in human pathology and aging: molecular mechanisms and perspectives. Cells. 2022;12(1):11. doi: 10.3390/cells12010011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Guo J, Huang X, Dou L, et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther. 2022;7(1):391. doi: 10.1038/s41392-022-01251-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Ma Y, Zheng L, Wang Y, Gao Y, Xu Y. Arachidonic acid in follicular fluid of PCOS induces oxidative stress in a human ovarian granulosa tumor cell line (KGN) and Upregulates GDF15 expression as a response. Front Endocrinol. 2022;13:865748. doi: 10.3389/fendo.2022.865748 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Wang Y, Che M, Xin J, Zheng Z, Li J, Zhang S. The role of IL-1β and TNF-α in intervertebral disc degeneration. Biomed Pharmacother. 2020;131:110660. doi: 10.1016/j.biopha.2020.110660 [DOI] [PubMed] [Google Scholar]
  • 94.Jang DI, Lee AH, Shin HY, et al. The Role of Tumor Necrosis Factor Alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. Int J Mol Sci. 2021;23(1):22. doi: 10.3390/ijms23010022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Piek A, Du W, de Boer RA, Silljé HHW. Novel heart failure biomarkers: why do we fail to exploit their potential? Crit Rev Clin Lab Sci. 2018;55(4):246–263. doi: 10.1080/10408363.2018.1460576 [DOI] [PubMed] [Google Scholar]
  • 96.Zhang BC, Zhang J, Sun L. In-depth profiling and analysis of host and viral microRNAs in Japanese flounder (Paralichthys olivaceus) infected with megalocytivirus reveal involvement of microRNAs in host-virus interaction in teleost fish. BMC Genomics. 2014;15(1):878. doi: 10.1186/1471-2164-15-878 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Delrue C, Speeckaert R, Delanghe JR, Speeckaert MM. Growth differentiation factor 15 (GDF-15) in kidney diseases. Adv Clin Chem. 2023;114:1–46. doi: 10.1016/bs.acc.2023.02.003 [DOI] [PubMed] [Google Scholar]
  • 98.Zhou Z, Liu H, Ju H, Chen H, Jin H, Sun M. Circulating GDF-15 in relation to the progression and prognosis of chronic kidney disease: a systematic review and dose-response meta-analysis. Eur J Int Med. 2023;110:77–85. doi: 10.1016/j.ejim.2023.01.026 [DOI] [PubMed] [Google Scholar]
  • 99.Moschovaki-Filippidou F, Steiger S, Lorenz G, et al. Growth differentiation factor 15 ameliorates anti-glomerular basement membrane glomerulonephritis in mice. Int J Mol Sci. 2020;22(1):21. doi: 10.3390/ijms22010021 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Hamon SM, Griffin TP, Islam MN, Wall D, Griffin MD, O’Shea PM. Defining reference intervals for a serum growth differentiation factor-15 (GDF-15) assay in a Caucasian population and its potential utility in diabetic kidney disease (DKD). Clin Chem Lab Med. 2019;57(4):510–520. doi: 10.1515/cclm-2018-0534 [DOI] [PubMed] [Google Scholar]
  • 101.Kageyama K, Iwasaki Y, Watanuki Y, et al. Growth differentiation factor-15 modulates adrenocorticotropic hormone synthesis in murine AtT-20 corticotroph cells. Peptides. 2022;155:170841. doi: 10.1016/j.peptides.2022.170841 [DOI] [PubMed] [Google Scholar]
  • 102.van Haalen H, Jackson J, Spinowitz B, Milligan G, Moon R. Impact of chronic kidney disease and anemia on health-related quality of life and work productivity: analysis of multinational real-world data. BMC Nephrol. 2020;21(1):88. doi: 10.1186/s12882-020-01746-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Perez-Gomez MV, Pizarro-Sanchez S, Gracia-Iguacel C, et al. Urinary Growth Differentiation Factor-15 (GDF15) levels as a biomarker of adverse outcomes and biopsy findings in chronic kidney disease. J Nephrol. 2021;34(6):1819–1832. doi: 10.1007/s40620-021-01020-2 [DOI] [PubMed] [Google Scholar]
  • 104.Carlsson AC, Nowak C, Lind L, et al. Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach. Ups J Med Sci. 2020;125(1):37–43. doi: 10.1080/03009734.2019.1696430 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Barma M, Khan F, Price RJG, et al. Association between GDF-15 levels and changes in vascular and physical function in older patients with hypertension. Aging Clin Exp Res. 2017;29:1055–1059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Mima A, Kitada M, Geraldes P, et al. Glomerular VEGF resistance induced by PKCδ/SHP-1 activation and contribution to diabetic nephropathy. FASEB j. 2012;26(7):2963–2974. doi: 10.1096/fj.11-202994 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Mima A, Nomura A, Fujii T. Current findings on the efficacy of incretin-based drugs for diabetic kidney disease: a narrative review. Biomed Pharmacothe. 2023;165:115032. doi: 10.1016/j.biopha.2023.115032 [DOI] [PubMed] [Google Scholar]
  • 108.Mima A, Yasuzawa T, Nakamura T, Ueshima S. Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes. Sci Rep. 2020;10(1):5775. doi: 10.1038/s41598-020-62579-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Lukaszyk E, Lukaszyk M, Koc-Zorawska E, Bodzenta-Lukaszyk A, Malyszko J. GDF-15, iron, and inflammation in early chronic kidney disease among elderly patients. Int Urol Nephrol. 2016;48(6):839–844. doi: 10.1007/s11255-016-1278-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Nalado AM, Olorunfemi G, Dix-Peek T, et al. Hepcidin and GDF-15 are potential biomarkers of iron deficiency anaemia in chronic kidney disease patients in South Africa. BMC Nephrol. 2020;21(1):415. doi: 10.1186/s12882-020-02046-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Laucyte-Cibulskiene A, Ward LJ, Ebert T, et al. Role of GDF-15, YKL-40 and MMP 9 in patients with end-stage kidney disease: focus on sex-specific associations with vascular outcomes and all-cause mortality. Biol Sex Differ. 2021;12(1):50. doi: 10.1186/s13293-021-00393-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Lewis GA, Rosala-Hallas A, Dodd S, et al. Characteristics associated with growth differentiation factor 15 in heart failure with preserved ejection fraction and the impact of pirfenidone. J Am Heart Assoc. 2022;11(14):e024668. doi: 10.1161/JAHA.121.024668 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Bansal N, Zelnick L, Go A, et al. Cardiac biomarkers and risk of incident heart failure in chronic kidney disease: the CRIC (Chronic Renal Insufficiency Cohort) study. J Am Heart Assoc. 2019;8(21):e012336. doi: 10.1161/JAHA.119.012336 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Natale P, Strippoli G. Sun-243 antiplatelet agents for chronic kidney disease: an updated Cochrane review. Kidney Int Rep. 2020;5(3):S299–S300. doi: 10.1016/j.ekir.2020.02.778 [DOI] [Google Scholar]
  • 115.Yilmaz H, Cakmak M, Darcin T, et al. Can serum Gdf-15 be associated with functional iron deficiency in hemodialysis Patients? Indian J Hematol Blood Transfus. 2016;32(2):221–227. doi: 10.1007/s12288-015-0551-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Shao Y, Wang H, Liu C, et al. Transforming growth factor 15 increased in severe aplastic anemia patients. Hematology. 2017;22(9):548–553. doi: 10.1080/10245332.2017.1311462 [DOI] [PubMed] [Google Scholar]
  • 117.Schechter A, Gafter-Gvili A, Shepshelovich D, et al. Post renal transplant anemia: severity, causes and their association with graft and patient survival. BMC Nephrol. 2019;20(1):51. doi: 10.1186/s12882-019-1244-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Thorsteinsdottir H, Salvador CL, Mjøen G, et al. Growth differentiation factor 15 in children with chronic kidney disease and after renal transplantation. Dis. Markers. 2020;2020:6162892. doi: 10.1155/2020/6162892 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.de Cos Gomez M, Benito Hernandez A, Garcia Unzueta MT, et al. Growth differentiation factor 15: a biomarker with high clinical potential in the evaluation of kidney transplant candidates. J Clin Med. 2020;9(12):4112. doi: 10.3390/jcm9124112 [DOI] [PMC free article] [PubMed] [Google Scholar]

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