Background: The increasing prevalence of kidney diseases has become a significant public health issue, with a global prevalence exceeding 10%. In order to accurately identify biochemical changes and treatment outcomes associated with kidney diseases, novel methods targeting specific genes have been discovered. Among these genes, leucine-rich α-2 glycoprotein 1 (LRG1) has been identified to function as a multifunctional pathogenic signaling molecule in multiple diseases, including kidney diseases. This study aims to provide a comprehensive overview of the current evidence regarding the roles of LRG1 in different types of kidney diseases. Summary: Based on a comprehensive review, it was found that LRG1 was upregulated in the urine, serum, or renal tissues of patients or experimental animal models with multiple kidney diseases, such as diabetic nephropathy, kidney injury, IgA nephropathy, chronic kidney diseases, clear cell renal cell carcinoma, end-stage renal disease, canine leishmaniosis-induced kidney disease, kidney fibrosis, and aristolochic acid nephropathy. Mechanistically, the role of LRG1 in kidney diseases is believed to be detrimental, potentially through its regulation of various genes and signaling cascades, i.e., fibronectin 1, GPR56, vascular endothelial growth factor (VEGF), VEGFR-2, death receptor 5, GDF15, HIF-1α, SPP1, activin receptor-like kinase 1-Smad1/5/8, NLRP3-IL-1b, and transforming growth factor β pathway. Key Messages: Further research is needed to fully comprehend the molecular mechanisms by which LRG1 contributes to the pathogenesis and pathophysiology of kidney diseases. It is anticipated that targeted treatments focusing on LRG1 will be utilized in clinical trials and implemented in clinical practice in the future.

Kidney diseases, which encompass acute kidney injury (AKI) and chronic kidney diseases (CKDs), are increasingly recognized as significant global public health concerns. The global prevalence of kidney diseases exceeds 10% [1]. As a vital organ, the kidney functions as the maintenance of electrolyte balance, the stability of blood pH, removal of metabolic waste, and reabsorption of nutrients and minerals for the body [2]. Additionally, the kidney also regulates blood pressure, vitamin D maturation, and erythropoiesis. Under the pathophysiological conditions (i.e., long-term starvation, fasting, and insulin resistance), the kidney can produce glucose through the action of gluconeogenesis. Heavy workload on the kidneys and exposure to various risk factors can cause the development and the progression of kidney diseases or renal injuries. Individuals with CKD are found to be associated with an increased risk of AKI, while AKI increases the susceptibility to developing CKD. In severe cases, AKI can lead to acute renal failure. On the other hand, CKD may inevitably progress into end-stage kidney disease (ESKD) [3, 4]. Both renal failure and ESKD seriously threaten the sufferer’s life. By 2040, CKD is projected to become the world's fifth leading cause of death [5].

To date, few pharmaceutical products are available for the treatment of AKI or CKD. In AKI, continuous renal replacement therapy is designed to maintain hydroelectrolyte balance and acid-base balance, as well as alleviate the symptoms of uremia in patients by continuously removing metabolites and fluids from the body [6]. Renal dialysis is the conventional strategy to treat advanced or the terminal-stage CKD [7]. Nevertheless, challenges remain in some uncontrolled cases, which dramatically increase the morbidity and mortality of the sufferers [8]. Therefore, additional studies are still warranted to address these diseases. At present, numerous therapeutic approaches have been explored to fight kidney diseases. Novel methods targeted with associated genes and cell-signaling processes have been found to provide the precise identification of biochemical changes and treatment outcomes of kidney diseases [9].

Leucine-rich α-2 glycoprotein 1 (LRG1), a secreted protein of the family of leucine-rich repeats (LRRs), functions as a multifunctional pathogenic signaling molecule in various diseases [10]. LRG1 can modulate the transforming growth factor β (TGF-β) pathway through a highly context-dependent manner, involving in the pathological angiogenesis [11]. TGF-β serves as an important pro-fibrotic growth factor that is activated in the process of AKI [12]. Furthermore, there exists a correlation between cellular responses and the onset of CKD [13]. Additionally, the involvement of angiogenesis in the pathophysiological progression of kidney diseases has been established [14]. Given the intimate association between the TGF-β pathway and the development of kidney diseases, it is plausible that LRG1 also assumes a crucial function in these conditions. Currently, since the absence of pertinent literature reviews examining the roles of LRG1 in kidney diseases, it is imperative to undertake a comprehensive review based on the existing evidence.

LRG1, originally separated from human serum in 1977, belongs to the leucine-rich repeating family [15]. It is composed of eight LRRs with a majority of 20–30 amino acid residues in length [16]. This gene is located on the short arm of chromosome 19, band 3, and region 13. The amino acid sequence of LRG1 contains 312 amino acids, which was confirmed in 1985 [17]. LRG1, a glycoprotein with 5 glycosylation sites, is 45 kDa in molecular weight with a 4.52 to 4.72 isoelectric point. According to predictions, LRG1 contains several loops connecting its leucine-rich C-terminal domain to its LRRs. Functionally, LRG1 participates in various cellular processes, e.g., signal transduction, cell differentiation, proliferation, migration, apoptosis, and cell cycle progression, etc [18]. Intracellularly, plasma LRG1 interacted with cytochrome c which is a small soluble electron carrier hemeprotein [19, 20]. Though the physiological function of LRG1 remains poorly understood, the LRG1 gene is one of the factors that promote vascular dysfunction and pathological angiogenesis. LRG1 has been found to regulate TGF-β signaling in a variety of diseases, switching the phenotype from a quiescent to an active angiogenic state [11]. Commonly, LRG1 binds to the TGF-β type II receptor accessory receptor endoglin and in conjunction with TGF-β, thus promoting the pro-angiogenic Smad1/5/8 cascade. The activin receptor-like kinase 1 (ALK1) and 5 (ALK5) are the two receptors through which TGF-β type II receptor initiates canonical signaling [21]. The LRG1 protein is capable of regulating the pathogenic neovascularization by transforming TGF-β cascade toward a proliferative pattern in endothelial cells [22]. However, LRG1 was also identified to modify the cell migratory machinery via the upstream modulation of noncanonical TGF-β signaling, e.g., FAK-ERK and Wnt/β-catenin pathway [23, 24].

According to published data, LRG1 has been implicated in the pathogenesis of multiple diseases, e.g., diabetes, cancer, and kidney diseases [19]. A variety of cellular targets are targeted by LRG1 to mediate pathogenic mechanisms. These include epithelial, endothelial, immune, age-related macular degeneration, and mesenchymal cells. Under homoeostatic conditions, LRG1 is produced primarily by hepatocytes and granulocytes with a concentration of 10–50 μg/mL in serum [25], but its plasma levels are often elevated during acute and chronic pathological states [19]. As reported, a different glycosylation pattern is observed in neutrophil-derived LRG1 and serum-derived LRG1 [26]. Confirmed by in situ co-hybridization and immunohistochemistry on laser-captured glomeruli, LRG1 was found to express in kidney endothelial cells [27], indicating LRG1 may involve in the development of renal diseases. The objective of this study was to provide a comprehensive review of the existing literature on LRG1, focusing specifically on its biological significance in kidney diseases.

Diabetes nephropathy is common renal disease associated with long terms of diabetes mellitus. Its complications include proteinuria, reduction in glomerular filtration, glomerular enlargement, and renal fibrosis [28]. In some certain regions, the prevalence of diabetes nephropathy in adults was recorded over 20% [29]. Diabetes nephropathy-associated heart failure with unchanged ejection fraction is the common causes of deaths and morbidity in patients with diabetes nephropathy. With the exception of renal replacement therapy, few therapeutic strategies were turned out to be ineffective for treating diabetes nephropathy. To obtain an effective, rapid, and noninvasive method for detecting DN early and predicting its prognosis, many biomarkers have been detected to participate in the pathophysiological mechanisms in diabetes nephropathy.

One such molecular is LRG1. As shown in Table 1, eight included studies reported the relationship between LRG1 and the development of diabetes nephropathy.

Table 1.

Role of LRG1 in diabetic nephropathy

Study/referenceStudy objectsKidney diseaseLRG1 expressionAssociated genes or pathwaysMain findings
Singh et al. [30] (2017) Patients (n = 220) Diabetic kidney disease Up in urine Activated FN1 LRG1 was 3.5 times more abundant in patients with type 1 diabetes than the healthy controls. LRG1 interacted with FN1, together contributed to the development of diabetic kidney disease 
Fu et al. [33] (2018) Cells and mice Diabetic nephropathy Up in glomerular endothelial cells and renal tissue (glomeruli) Activated GPR56 High glucose conditions elevated both LRG1 and GPR56 expressions. These two genes also increased in STZ glomeruli. They were implicated in regulation of angiogenesis 
Haku et al. [35] (2018) Cells and mice Diabetic nephropathy Up in glomerular endothelial cells Activated VEGF and VEGFR-2 LRG1 directly binds to the TGF-β accessory receptor ENG and TGF-β receptor-II. LRG1 played roles in the development of diabetic nephropathy by enhancing aberrant angiogenesis and glomerular hypertrophy 
Hong et al. [27] (2019) Patients, cells, and mice Diabetic kidney disease Up in plasma ALK1-Smad1/5/8 activation LRG1 predominantly localized in glomerular endothelial cells. Its expression increased in the diabetic kidneys by activating ALK1-Smad1/5/8. Inhibition of LRG1 significantly alleviated diabetes-induced glomerular angiogenesis and podocyte loss. Elevation of plasma LRG1 was correlated to worse renal outcome in patients with DM 
Gurung et al. [32] (2021) Patients (n = 1,813) Diabetic nephropathy Up in plasma SNP (rs4806985) High plasma LRG1 increased the risk of longitudinal decline in kidney function. SNP (rs4806985) was robustly associated with the expression of LRG1 
Jiang et al. [38] (2022) Cells and mice Diabetic nephropathy Up in renal tissues and cells Activated TGF-βR1 and death receptor 5 (DR5) LRG1-enriched extracellular vesicles activated macrophages via a TGF-βR1-dependent process. TNF-related apoptosis-inducing ligand-enriched extracellular vesicles induced apoptosis in injured TECs via a death receptor 5 (DR5)-dependent process 
Liu et al. [31] (2023) Patients (n = 134) Type 2 diabetes-induced ESKD Up in urine TGF-β signaling After adjustment of the common risk factors, patients with high level of LRG1 had a 1.91-fold (95% CI: 1.04–3.50, p= 0.04) increased risk of progression to ESKD. Urine LRG1 was correlated to rapid declination of kidney function and progression to macroalbuminuria 
Mohammad et al. [37] (2023) Cells and rats Diabetic nephropathy Up in renal tissues and cells Activated TGF-β1/ALK1 LRG1 increased in rat model of diabetic nephropathy, while metformin reversed this tendency, which might be correlated to the inhibition of TGF-β1/ALK1-induced angiogenesis and the protection of ultrastructural changes 
Study/referenceStudy objectsKidney diseaseLRG1 expressionAssociated genes or pathwaysMain findings
Singh et al. [30] (2017) Patients (n = 220) Diabetic kidney disease Up in urine Activated FN1 LRG1 was 3.5 times more abundant in patients with type 1 diabetes than the healthy controls. LRG1 interacted with FN1, together contributed to the development of diabetic kidney disease 
Fu et al. [33] (2018) Cells and mice Diabetic nephropathy Up in glomerular endothelial cells and renal tissue (glomeruli) Activated GPR56 High glucose conditions elevated both LRG1 and GPR56 expressions. These two genes also increased in STZ glomeruli. They were implicated in regulation of angiogenesis 
Haku et al. [35] (2018) Cells and mice Diabetic nephropathy Up in glomerular endothelial cells Activated VEGF and VEGFR-2 LRG1 directly binds to the TGF-β accessory receptor ENG and TGF-β receptor-II. LRG1 played roles in the development of diabetic nephropathy by enhancing aberrant angiogenesis and glomerular hypertrophy 
Hong et al. [27] (2019) Patients, cells, and mice Diabetic kidney disease Up in plasma ALK1-Smad1/5/8 activation LRG1 predominantly localized in glomerular endothelial cells. Its expression increased in the diabetic kidneys by activating ALK1-Smad1/5/8. Inhibition of LRG1 significantly alleviated diabetes-induced glomerular angiogenesis and podocyte loss. Elevation of plasma LRG1 was correlated to worse renal outcome in patients with DM 
Gurung et al. [32] (2021) Patients (n = 1,813) Diabetic nephropathy Up in plasma SNP (rs4806985) High plasma LRG1 increased the risk of longitudinal decline in kidney function. SNP (rs4806985) was robustly associated with the expression of LRG1 
Jiang et al. [38] (2022) Cells and mice Diabetic nephropathy Up in renal tissues and cells Activated TGF-βR1 and death receptor 5 (DR5) LRG1-enriched extracellular vesicles activated macrophages via a TGF-βR1-dependent process. TNF-related apoptosis-inducing ligand-enriched extracellular vesicles induced apoptosis in injured TECs via a death receptor 5 (DR5)-dependent process 
Liu et al. [31] (2023) Patients (n = 134) Type 2 diabetes-induced ESKD Up in urine TGF-β signaling After adjustment of the common risk factors, patients with high level of LRG1 had a 1.91-fold (95% CI: 1.04–3.50, p= 0.04) increased risk of progression to ESKD. Urine LRG1 was correlated to rapid declination of kidney function and progression to macroalbuminuria 
Mohammad et al. [37] (2023) Cells and rats Diabetic nephropathy Up in renal tissues and cells Activated TGF-β1/ALK1 LRG1 increased in rat model of diabetic nephropathy, while metformin reversed this tendency, which might be correlated to the inhibition of TGF-β1/ALK1-induced angiogenesis and the protection of ultrastructural changes 

eGFR, estimated glomerular filtration rate; AKI, acute kidney injury; CKD, chronic kidney disease; FN1, fibronectin 1.

Consistently, all the eight eligible studies demonstrated that the level LRG1 was elevated in urine, serum, or kidney tissues of a condition of diabetes nephropathy. There were three clinical studies in this section. Singh et al. [30] recruited 220 young patients (3–18 years of age) with type 1 diabetes kidney disease and found that the expression of LRG1 was increased in urine samples. LRG1 level was 3.5 times more abundant in patients with type 1 diabetes than the healthy controls. Mechanistically, high level of LRG1 might interact with its associated protein fibronectin 1, together contributed to the development of diabetic kidney disease. Patients with type 1 diabetes might present with membrane damage in lysosomes of renal tubular epithelial cells (TECs). The authors concluded that LRG1 might serve as a promising inflammation and neovascularization biomarker in diabetic kidney disease. In line with the findings by Singh et al., Liu et al. [31] also reported that LRG1 was upregulated in the urine of patients with type 2 diabetes-induced ESKD. After adjustment of the common risk factors, patients with high level of LRG1 had a 1.91-fold (95% CI: 1.04–3.50, p = 0.04) increased risk of progression to ESKD. Urine LRG1 was correlated to rapid declination of kidney function and progression to macroalbuminuria. The possible pathophysiological mechanisms linking urine LRG1 and progressive diabetic kidney disease might be associated with amplification of the TGF-β signaling cascade in the diabetic kidneys. In addition to the high level of LRG1 in urine, in a large-sample study (n = 1,813) developed by Gurung et al. [32], it demonstrated that LRG1 was elevated in plasma of patients with diabetic nephropathy. The author further found that high plasma LRG1 increased the risk of longitudinal decline in kidney function, while SNP (rs4806985) was robustly associated with the expression of LRG1. It was possible that plasma LRG1 might play a causal role in progression of diabetic nephropathy at an early stage of CKD. The aforementioned three clinical studies have demonstrated that patients with diabetic nephropathy exhibited heightened levels of LRG1 in both urine and plasma.

Five experimental studies reported the roles of LRG1 in cell or animal models of diabetic kidney disease. All these included studies confirmed LRG1 was increased in glomerular endothelial cells, serum, urine, and renal tissues of the in vitro and in vivo models. In the study by Fu et al. [33], upregulated LRG1 in glomerular endothelial cells and renal tissue (glomeruli) was observed in high glucose-mediated cells and streptozotocin-induced diabetic mice. High-glucose conditions elevated both LRG1 and GPR56 expression. These two genes also increased in STZ glomeruli, implicating in regulation of angiogenesis in the glomerulopathy of diabetic mice. LRG1 has been found to directly bind to endoglin, a TGF-β accessory receptor, together form the complex bind to TGF-β receptor-II (TβRII) [11]. Vascular endothelial growth factor (VEGF) functions to regulate abnormal angiogenesis. The glomerular expression of VEGF was found to contribute to early stage diabetic nephropathy [34]. Haku et al. [35] found that the expression of LRG1 raised in glomerular endothelial cells in diabetic db/db mice. Increased LRG1 expression might prior to the elevation of VEGF expression. The authors revealed that LRG1 played roles in the development of diabetic nephropathy by enhancing aberrant angiogenesis and glomerular hypertrophy. LRG1 promotes neovascularization by enhancing endothelial TGF-β/ALK1 signaling [36]. Hong et al. [27] showed that LRG1 level was increased in plasma of diabetic mice. LRG1 predominantly localized in glomerular endothelial cells. Its expression increased in the diabetic kidneys by activating ALK1-Smad1/5/8. Inhibition of LRG1 significantly alleviated diabetes-induced glomerular angiogenesis and podocyte loss. Elevation of plasma LRG1 was correlated to worse renal outcome in patients with diabetic kidney disease. Consistent with the study by Hong et al. on the association between LRG1 and ALK1, Mohammad et al. [37] reported that the LRG1 expression was up in renal tissues and cells. LRG1 increased in rat model of diabetic nephropathy, while metformin reversed this tendency, which might be correlated to the inhibition of TGF-β1/ALK1-induced angiogenesis and the protection of ultrastructural changes. Death receptor 5 (DR5) is found to correlate with kidney function decline. A recent study reported by Jiang et al. [38] suggested that LRG1 was up in renal tissues and cells. The authors indicated that LRG1-enriched extracellular vesicles activated macrophages via a TGF-βR1-dependent process. TNF-related apoptosis-inducing ligand-enriched extracellular vesicles induced apoptosis in injured TECs via a DR5-dependent process. LRG1/TGF-βR1 signaling could elevate tumor necrosis factor-related apoptosis-inducing ligand expression in macrophages. These eligible studies have indicated that elevated LRG1 expression contributes to the progression of diabetes mellitus, thereby offering potential insights for the development of improved therapeutic interventions.

AKI is one of the common kidney diseases and is associated with the subsequent progression of CKD. It occurs in nearly half of patients with critically ill, correlating with increased in-hospital mortality and long-term mortality postdischarge [39]. Five included studies reported the roles of LRG1 in kidney injury (Table 2). Three of them were the clinical studies, while the remainder two studies were experimental designed. All of five included studies confirmed that LRG1 was upregulated in the serum, urine, and kidney tissues of the patients or experimental models of kidney injury.

Table 2.

Role of LRG1 in kidney injury

Study/referenceStudy objectsKidney diseaseLRG1 expressionAssociated genes or pathwaysMain findings
Hashida et al. [40] (2017) Patients (n = 20) Sepsis-induced AKI Up in serum NA LRG1 was significantly upregulated in the serum of patients with sepsis-associated AKI than those without sepsis (p< 0.05). LRG1 might be a novel substance associated with sepsis 
Lee et al. [46] (2018) Cells and mice Proteinuria-induced renal tubular injury (intraperitoneal injection of pH 7.0 and low-endotoxin bovine serum albumin) Up in urine Activated NLRP3-IL-1b pathway Urinary LRG was produced in renal TECs, which released during proteinuria-induced renal damage. LRG could be blocked by IL-1 receptor antagonist 
Jiang et al. [43] (2020) Patients (n = 60) Cisplatin-induced AKI Up in kidney tissue and urine GDF15 and SPP1 LRG1 might be one of the candidate urinary markers of kidney injury after cisplatin treatment. LRG1, combined with GDF15 and SPP1, involved in the development of cisplatin-induced kidney injury 
Muk et al. [49] (2020) Mouse, cells, and patients Chorioamnionitis-induced kidney injury Up in the kidney tissues HIF-1α activation Both mRNA and protein levels of LRG1 were elevated in the kidneys of lipopolysaccharide pigs at birth and associated with plasma creatinine. Kidney injury might be caused by LRG1-mediated hypoxia via HIF-1α activation 
Popova et al. [45] (2022) Patients (n = 35) Kidney injury induced by kidney transplant Up in serum and urine NA Upregulation of serum and urine LRG1 were significantly correlated to kidney transplant injury and functional deterioration 
Study/referenceStudy objectsKidney diseaseLRG1 expressionAssociated genes or pathwaysMain findings
Hashida et al. [40] (2017) Patients (n = 20) Sepsis-induced AKI Up in serum NA LRG1 was significantly upregulated in the serum of patients with sepsis-associated AKI than those without sepsis (p< 0.05). LRG1 might be a novel substance associated with sepsis 
Lee et al. [46] (2018) Cells and mice Proteinuria-induced renal tubular injury (intraperitoneal injection of pH 7.0 and low-endotoxin bovine serum albumin) Up in urine Activated NLRP3-IL-1b pathway Urinary LRG was produced in renal TECs, which released during proteinuria-induced renal damage. LRG could be blocked by IL-1 receptor antagonist 
Jiang et al. [43] (2020) Patients (n = 60) Cisplatin-induced AKI Up in kidney tissue and urine GDF15 and SPP1 LRG1 might be one of the candidate urinary markers of kidney injury after cisplatin treatment. LRG1, combined with GDF15 and SPP1, involved in the development of cisplatin-induced kidney injury 
Muk et al. [49] (2020) Mouse, cells, and patients Chorioamnionitis-induced kidney injury Up in the kidney tissues HIF-1α activation Both mRNA and protein levels of LRG1 were elevated in the kidneys of lipopolysaccharide pigs at birth and associated with plasma creatinine. Kidney injury might be caused by LRG1-mediated hypoxia via HIF-1α activation 
Popova et al. [45] (2022) Patients (n = 35) Kidney injury induced by kidney transplant Up in serum and urine NA Upregulation of serum and urine LRG1 were significantly correlated to kidney transplant injury and functional deterioration 

eGFR, estimated glomerular filtration rate; AKI, acute kidney injury; CKD, chronic kidney disease.

In one of the three clinical studies, Hashida et al. [40] reported that LRG1 was significantly upregulated in the serum of patients with sepsis-induced AKI than those without sepsis (sample size, p < 0.05). Sepsis is a life-threatening condition induced by dysregulated host responses to infection [41]. Proteome analysis on plasma has been found to be a novel biomarker for diagnosing with sepsis. In the study by Hashida et al., the authors identified 400 proteins from the plasma in AKI patients with sepsis and concluded that LRG1 might be a novel substance associated with sepsis and sepsis-induced AKI. Cisplatin is one of the common and effective treatments for various types of cancers, but the complications of nephrotoxicity limit its use [42]. Jiang et al. [43] suggested that LRG1 was elevated in the renal tissues and urine of patients with cisplatin-induced kidney injury. They implicated that LRG1 might be one of the candidate urinary markers of kidney injury after cisplatin treatment. LRG1, combined with GDF15 and SPP1, involved in the development of cisplatin-induced kidney injury. This study may help design the new methods to monitor the kidney function in cisplatin-based chemotherapy. Kidney transplantation is an efficient therapy for patients with end-stage renal disease, but transplantation-associated kidney injury is a non-negligible issue [44]. As aforementioned, LRG1 has been found to serve as an effective biomarker of kidney injury. In line with above findings, Popova et al. [45] also reported LRG1 was up in serum and urine of patients with kidney injury induced by kidney transplant (n = 35). A positive correlation was found between serum and urine LRG1 (r = 0.41; 95% CI: 0.09 to 0.66; p = 0.01). The aforementioned three clinical studies have provided evidence regarding the significance of serum, urine, and renal tissue LRG1 as a marker for kidney injury in sepsis, chemotherapy, and kidney transplant.

There were two in vitro and in vivo study reported biological effects of LRG1 in kidney injury. Lee et al. [46] established the cellular and mice models of renal tubular injury. They found that urinary LRG was produced in renal TECs, which released during proteinuria-induced renal damage. LRG could be blocked by interleukin-1 (IL-1) receptor antagonist. LRG played its roles in renal cell injury by activating NLRP3-IL-1b pathway. LRG expression can be induced by inflammatory cytokines, including IL-6, IL-1b, and tumor necrosis factor-α (TNFα) [47]. LRG protein levels are elevated not only in serum but also in secreted materials from the inflamed tissues [48]. The study by Lee et al. [46] suggested that urinary LRG might be a potential biomarker for renal tubule injury and the interstitial inflammation in renal diseases. Another study developed by Muk et al. [49] demonstrated that both mRNA and protein levels of LRG1 were elevated in the kidneys of lipopolysaccharide pigs (chorioamnionitis-induced kidney injury) at birth and associated with plasma creatinine. Additionally, exposure to prenatal endotoxins may result in renal inflammation during fetal and postnatal stages, potentially leading to kidney injury through LRG1-mediated hypoxia via HIF-1α activation. Lee et al. [46] reported that pro-inflammatory cytokine production (i.e., IL-1β) during renal tubular injury might be the major mechanism to increase urinary LRG. IL-1β induces LRG expression in renal tubular cells and LRG excretion in urine. In line with this finding, Muk et al. [49] implied that upregulated LRG1 expression was associated with renal inflammation, hypoxia, and immune cell infiltration during the process of AKI. Therefore, the possible pathophysiological mechanisms linking LRG1 upregulation and AKI might be closely correlated to its effects on renal inflammation. These two experimental studies have further illustrated the potential of LRG1 as a diagnostic and therapeutic target for kidney injury associated with inflammation. However, the underlying mechanisms of this primary glomerulonephritis remain uncertain at present.

IgA nephropathy (IgAN) is an inflammatory and immune-associated CKD [50]. In this review, three clinical studies reported the expression of LRG1 in patients with IgAN. Khositseth et al. [51] conducted a case reported study with a case of IgAN associated with Hodgkin’s disease in a child. The LRG1 expression (1.4343) in the urinary was high (up in urine) before treatments with CHOP chemotherapy and enalapril, while LRG1 decreased after 1 month (0.7459) and 4 months (0.3757) of treatments. Khositseth et al. suggested that proteomic technology for detecting LRG1 expression might effectively monitor therapeutic response of IgAN. Consistent with the study by Khositseth et al., a recent clinical study developed by Liu et al. [52] also demonstrated that LRG1 expression was elevated in patients with IgAN than the controls. The expression of LRG1 level was increased in renal tissues of IgAN patients with heavy fibrosis and heavy inflammatory cell infiltration. The authors implicated that LRG1 inhibited fibronectin secretion by suppressing TGF-β1 expression. TGF-β1 was found to serve as an important factor to produce pro-fibrotic proteins [53]. Renal interstitial fibrosis may cause by the actions of TGF-β1 on renal TECs and endothelial cells. Of note, the findings by Kalantari et al. [54] are incongruent with the above two included studies. The authors evidenced that LRG1 expression was low in the urinary of patients with IgAN. There was a positive association between LRG1 expression and the value of eGFR (p < 0.001). Furthermore, the expression of LRG1 was found to be linked to the differentiation of brown fat cells. However, the inconsistent findings in this regard remain unclear. It is postulated that the involvement of different races and study populations may contribute to this phenomenon.

CKD, ranked as the 10th leading cause of mortality, affects a substantial proportion of the global population, reaching up to 13% [55]. The identification of accurate biomarkers for early diagnosing of CKD is a real challenge. Within the topic of this review, we identified two large-sample clinical studies reported the roles of LRG1 in the development of CKD. Both of two studies indicated the level of LRG1 was upregulated in serum of plasma of the patients with CKD. Liu et al. [16] recruited 1,226 patients with CKD and found that patients with albuminuria progression and CKD progression had higher plasma LRG1 levels at baseline. LRG1 independently predicted both albuminuria progression and CKD progression above traditional risk factors (i.e., eGFR and urine albumin-to-creatinine ratio). In line with this study, Low et al. [56] showed that increase in skeletal muscle mass ameliorated the effect of pigment epithelium-derived factor (PEDF) and LRG1 on CKD progression. PEDF, a secreted glycoprotein from the serpin family, has been confirmed to function as an anti-inflammatory, antioxidant, and anti-angiogenic factor [57]. PEDF has emerged as a novel biomarker with potential implications in renal decline, particularly in chronic kidney disease (CKD) [58]. Within the kidney, PEDF may confer reno-protection by mitigating fibrosis, inflammation, vascular hyper-permeability, and podocytes renal cell apoptosis induced by advanced glycation end products [59]. Conversely, plasma levels of PEDF may rise as a compensatory mechanism for diminished kidney-specific PEDF levels. A previous study [60] demonstrated decreased PEDF expression in the kidneys of streptozotocin-induced diabetic rats compared to nondiabetic rats. At present, only one clinical study [56] reported the roles of PEDF and LRG1 in CKD development. The authors found that plasma PEDF and LRG1 mediated the negative association between higher skeletal muscle mass index and CKD progression, which might be driven by inflammation. Given that PEDF is synthesized by a variety of cell types including hepatocytes, adipocytes, and muscle cells, while LRG1 is primarily synthesized by the liver, it is conceivable that dysfunctional adipocytes or hepatocytes could potentially lead to a systemic increase in inflammatory activity, as evidenced by elevated levels of plasma PEDF and LRG1, thereby contributing to the progression of CKD. Collectively, the concurrent involvement of PEDF and LRG1 in CKD progression may be attributed to their ability to enhance the inflammatory response. The aforementioned studies provided evidence indicating that elevated levels of plasma LRG1 are associated with the progression of CKD.

Moreover, within the scope of this subject, we also identified six additional studies that reported on the correlation between LRG1 expression and various other kidney diseases (Table 3). Hong et al. [61] evidenced that LRG1 was upregulated in kidney tissue samples of clear cell renal cell carcinoma (ccRCC) patients (n = 528). The methylation level of LRG1 was dramatically declined in ccRCC. LRG1 was negatively associated with the survival of ccRCC patients. LRG1 might promote ccRCC progression via the TGF-β pathway. LRG1 was found to express in plasma, leukocytes, proximal tubule, and inflammatory cells [62]. It upregulated in the plasma, peripheral blood leukocytes, and kidney of patients with lupus nephritis (sample size: 101). LRG1 suppressed the late apoptosis, promoted proliferation, and regulated the expression of both inflammatory factors and cytokines [62]. Yang et al. [63] investigated the roles of LRG1 in patients with ESKD (n = 169). The authors found that LRG1 was up in plasma of ESKD patients. LRG1 expression was significantly associated with the presence of peripheral arterial occlusive disease and cardiovascular disease in patients with ESKD. LRG1 level positively was correlated to IL-6, hsCRP, and advanced T-cell differentiation. In a dog model of canine leishmaniosis-induced kidney disease, Gonzalez et al. [64] implicated that LRG1 was elevated in urinary expression. LRG1 was one of the 12 discriminant variables found in dogs with renal disease induced by leishmaniosis. Hong et al. [65] showed that high level LRG1 in renal tissues cells might be correlated to the progression of kidney fibrosis. They also indicated that LRG1 might serve as an important amplifier of tubulointerstitial TGF-β/Smad3 signal transduction that enhanced renal fibrosis in CKD. Thus, suppression of LRG1 effectively reduced TGF-β signaling. Consistently, Jiang et al. [66] showed that LRG1 was upregulated in the renal tissues as well as the cells in an experimental model mimicked aristolochic acid nephropathy. LRG1-enriched extracellular vesicles induced the injury and apoptosis of TECs and apoptosis via a TGF-βR1-dependent process. In agreement, the above six included studies demonstrated that LRG1 was significantly increased in the plasma, urine, renal tissues and cells, either in animal or human. Activation of TGF-β, TGF-βR1, and their associated genes of pathways played an essential role in this action.

Table 3.

Role of LRG1 in other kidney diseases

Study/referenceStudy objectsKidney diseaseLRG1 expressionAssociated genes or pathwaysMain findings
Khositseth et al. [51] (2007) Patients (n = 1) IgAN Up in urine NA A case of IgAN associated with Hodgkin’s disease in a child. The LRG1 expression (1.4343) in the urinary was high before treatments with CHOP chemotherapy and enalapril, while LRG1 decreased after 1 month (0.7459) and 4 months (0.3757) of treatments 
Kalantari et al. [54] (2013) Patients (n = 13) IgA nephropathy Down in urine NA LRG1 expression was low in the urinary of patients with IgAN. There was a positive association between LRG1 expression and the value of eGFR (p< 0.001). LRG1 expression was associated with the brown fat cell differentiation 
Liu et al. [52] (2021) Patients (n = 141) IgAN Up in plasma and renal tissues Inhibited TGF-β1 The expression of LRG1 level increased in renal tissues of IgAN patients with heavy fibrosis and heavy inflammatory cell infiltration. LRG1 expression was also elevated in patients with IgAN than the controls. LRG1 inhibited fibronectin secretion by suppressing TGF-β1 expression 
Liu et al. [16] (2017) Patients (n = 1,226) CKD (inclusion criteria: adult patients who aged 21 years and older with type 2 diabetes) Up in serum NA Patients with albuminuria progression and CKD progression had higher plasma LRG1 levels at baseline. LRG1 independently predicted both albuminuria progression and CKD progression above traditional risk factors (i.e., eGFR and urine albumin-to-creatinine ratio) 
Low et al. [56] (2021) Patients (n = 1,272) CKD (inclusion criteria: patients with type 2 diabetes, having greater than two eGFR readings and more than 1 year of follow-up) Up in plasma NA Increase in skeletal muscle mass ameliorated the effect of pigment epithelium-derived factor (PEDF) and LRG1 on CKD progression 
Hong et al. [61] (2020) Patients (n = 528) ccRCC Up in ccRCC kidney tissue Activated TGF-β pathway LRG1 upregulated in ccRCC kidney tissue samples. The methylation level of LRG1 was dramatically declined in ccRCC. LRG1 was negatively associated with the survival of ccRCC patients. LRG1 might promote ccRCC progression via the TGF-β pathway 
Yang et al. [62] (2020) Patients (n = 101) Lupus nephritis Up in plasma and kidney NA LRG1 was found to express in plasma, leukocytes, proximal tubule, and inflammatory cells. It upregulated in the plasma, peripheral blood leukocytes, and kidney of patients with lupus nephritis. LRG1 suppressed the late apoptosis, promoted proliferation, and regulated the expression of both inflammatory factors and cytokines 
Yang et al. [63] (2020) Patients (n = 169) End-stage kidney disease (ESKD) Up in plasma IL-6 and hsCRP LRG1 expression was significantly associated with the presence of peripheral arterial occlusive disease and cardiovascular disease in patients with ESKD. LRG1 level positively correlated to IL-6, hsCRP, and advanced T-cell differentiation 
Gonzalez et al. [64] (2022) Dogs Canine leishmaniosis-induced kidney disease Up in urinary expression NA LRG1 was one of the 12 discriminant variables found in dogs with renal disease induced by leishmaniosis 
Hong et al. [65] (2022) Cells and mice Kidney fibrosis Up in renal tissues Activated TGF-β/Smad3 LRG1 served as an important amplifier of tubulointerstitial TGF-β/Smad3 signal transduction that enhanced renal fibrosis in CKD. Suppression of LRG1 effectively reduced TGF-β signaling 
Jiang et al. [66] (2022) Cells and mice Aristolochic acid nephropathy Up in renal tissues and cells Activated TGF-βR1 LRG1-enriched extracellular vesicles induced the injury and apoptosis of TECs and apoptosis via a TGF-βR1-dependent process 
Study/referenceStudy objectsKidney diseaseLRG1 expressionAssociated genes or pathwaysMain findings
Khositseth et al. [51] (2007) Patients (n = 1) IgAN Up in urine NA A case of IgAN associated with Hodgkin’s disease in a child. The LRG1 expression (1.4343) in the urinary was high before treatments with CHOP chemotherapy and enalapril, while LRG1 decreased after 1 month (0.7459) and 4 months (0.3757) of treatments 
Kalantari et al. [54] (2013) Patients (n = 13) IgA nephropathy Down in urine NA LRG1 expression was low in the urinary of patients with IgAN. There was a positive association between LRG1 expression and the value of eGFR (p< 0.001). LRG1 expression was associated with the brown fat cell differentiation 
Liu et al. [52] (2021) Patients (n = 141) IgAN Up in plasma and renal tissues Inhibited TGF-β1 The expression of LRG1 level increased in renal tissues of IgAN patients with heavy fibrosis and heavy inflammatory cell infiltration. LRG1 expression was also elevated in patients with IgAN than the controls. LRG1 inhibited fibronectin secretion by suppressing TGF-β1 expression 
Liu et al. [16] (2017) Patients (n = 1,226) CKD (inclusion criteria: adult patients who aged 21 years and older with type 2 diabetes) Up in serum NA Patients with albuminuria progression and CKD progression had higher plasma LRG1 levels at baseline. LRG1 independently predicted both albuminuria progression and CKD progression above traditional risk factors (i.e., eGFR and urine albumin-to-creatinine ratio) 
Low et al. [56] (2021) Patients (n = 1,272) CKD (inclusion criteria: patients with type 2 diabetes, having greater than two eGFR readings and more than 1 year of follow-up) Up in plasma NA Increase in skeletal muscle mass ameliorated the effect of pigment epithelium-derived factor (PEDF) and LRG1 on CKD progression 
Hong et al. [61] (2020) Patients (n = 528) ccRCC Up in ccRCC kidney tissue Activated TGF-β pathway LRG1 upregulated in ccRCC kidney tissue samples. The methylation level of LRG1 was dramatically declined in ccRCC. LRG1 was negatively associated with the survival of ccRCC patients. LRG1 might promote ccRCC progression via the TGF-β pathway 
Yang et al. [62] (2020) Patients (n = 101) Lupus nephritis Up in plasma and kidney NA LRG1 was found to express in plasma, leukocytes, proximal tubule, and inflammatory cells. It upregulated in the plasma, peripheral blood leukocytes, and kidney of patients with lupus nephritis. LRG1 suppressed the late apoptosis, promoted proliferation, and regulated the expression of both inflammatory factors and cytokines 
Yang et al. [63] (2020) Patients (n = 169) End-stage kidney disease (ESKD) Up in plasma IL-6 and hsCRP LRG1 expression was significantly associated with the presence of peripheral arterial occlusive disease and cardiovascular disease in patients with ESKD. LRG1 level positively correlated to IL-6, hsCRP, and advanced T-cell differentiation 
Gonzalez et al. [64] (2022) Dogs Canine leishmaniosis-induced kidney disease Up in urinary expression NA LRG1 was one of the 12 discriminant variables found in dogs with renal disease induced by leishmaniosis 
Hong et al. [65] (2022) Cells and mice Kidney fibrosis Up in renal tissues Activated TGF-β/Smad3 LRG1 served as an important amplifier of tubulointerstitial TGF-β/Smad3 signal transduction that enhanced renal fibrosis in CKD. Suppression of LRG1 effectively reduced TGF-β signaling 
Jiang et al. [66] (2022) Cells and mice Aristolochic acid nephropathy Up in renal tissues and cells Activated TGF-βR1 LRG1-enriched extracellular vesicles induced the injury and apoptosis of TECs and apoptosis via a TGF-βR1-dependent process 

eGFR, estimated glomerular filtration rate; AKI, acute kidney injury; CKD, chronic kidney disease.

This review highlights the crucial functions of LRG1 on the pathogenesis of diverse kidney diseases. LRG1 was commonly upregulated in kidney diseases, including diabetic nephropathy, kidney injury, IgAN, CKD, ccRCC, end-stage renal disease, canine leishmaniosis-induced kidney disease, kidney fibrosis, and aristolochic acid nephropathy. A study [37] indicated that metformin protected against diabetic nephropathy. The nephroprotective effect of metformin was speculated to mediate by downregulating of LRG1 and TGF-β1/ALK1-induced renal angiogenesis. This review highlighted that overactivation of LRG1 has been associated with the development of various kidney diseases, while inhibition of LRG1 expression significantly prevented these diseases. Therefore, future drugs or therapy-targeted LRG1 may provide a promising therapeutic direction against multiple kidney diseases. Further preclinical and clinical studies are warranted to investigate the effectiveness and safety of LRG1 inhibitors for treating kidney diseases.

As shown in Figure 1, LRG1 exerts a deleterious influence on kidney diseases by regulating multiple associated genes and signaling cascades, i.e., fibronectin 1, GPR56, VEGF, VEGFR-2, DR5, GDF15, HIF-1α, SPP1, ALK1-Smad1/5/8, NLRP3-IL-1b, and TGF-β pathway. Through comprehensive and thorough investigations in the future, the intricate molecular mechanisms underlying LRG1 in the development and pathophysiology of kidney diseases will be comprehensively elucidated. Consequently, therapeutic interventions targeting LRG1 are anticipated to be implemented in clinical trials and subsequently incorporated into clinical practice.

Fig. 1.

Molecular mechanisms underlying the roles of LRG1 on the development of various types of kidney diseases.

Fig. 1.

Molecular mechanisms underlying the roles of LRG1 on the development of various types of kidney diseases.

Close modal

The authors declare that they have no competing interests.

This study was supported by the Health Science and Technology Project of Guangzhou City, Guangdong Province (Grant No. 20231A011015, for Jingwei Zhang).

C.Y.C., J.W.Z., and T.Y. contributed to conceive and design the study. J.L. and H.Y.F. performed the systematic searching. C.Y.C. and T.Y. extracted the data. H.Y.F. wrote the manuscript. C.Y.C. supervised the manuscript. Y.F.J. contributed to the revision of the manuscript. All of the authors read and approved the final manuscript.

Additional Information

Chunyan Chen, Jingwei Zhang, and Tao Yu contributed equally to this work.

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