Home Leucine-rich α-2-glycoprotein 1 can be a novel angiogenic mediator in autosomal dominant polycystic kidney disease
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Leucine-rich α-2-glycoprotein 1 can be a novel angiogenic mediator in autosomal dominant polycystic kidney disease

  • Hazal Fatma Erdogan ORCID logo , Oguzhan Ozcan ORCID logo EMAIL logo , Ibrahim Dogan ORCID logo , Hamdi Oguzman ORCID logo and Faruk Hilmi Turgut ORCID logo
Published/Copyright: March 20, 2025
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Turkish Journal of Biochemistry
From the journal Turkish Journal of Biochemistry Volume 50 Issue 2

Abstract

Objectives

In the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), hypoxia-associated angiogenesis is increasingly considered a significant mechanism. We aimed to assess serum and urine leucine-rich α-2-glycoprotein 1 (LRG1) levels and their correlation with vascular endothelial growth factor A (VEGF-A), hypoxia-inducible factor 1-alpha (HIF-1α), and disease severity to explore LRG1’s role as a biochemical marker in ADPKD-related angiogenesis.

Methods

The study involved 67 ADPKD patients and 25 healthy controls. The ADPKD-I group comprised 40 patients with an estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) >60, and the ADPKD-II group comprised 27 patients with an eGFR <60. Height-adjusted total kidney volume (hTKV) was calculated from magnetic resonance (MR) images. Serum levels of LRG1, VEGF-A, HIF-1α, and urine LRG1 levels were assayed by ELISA, and urinary albumin levels were measured by the immunoturbidimetric method. Urine LRG and albumin levels were calculated by normalizing the urine creatinine ratio.

Results

The levels of serum LRG1 were remarkably higher only in the ADPKD-II group compared to controls (p<0.025). Serum HIF-1α and VEGF-A levels were significantly elevated in both ADPKD-I and ADPKD-II groups compared to controls (p = 0.039, p = 0.029, p<0.001, and p<0.001, respectively); however, there was no notable difference between two groups. Urinary LRG1 and albumin excretion levels were notably higher in both ADPKD groups than in controls but the highest in the ADPKD-II group. In the ADPKD-I group, urine LRG1 correlated positively with urinary albumin excretion (r = 0.338, p = 0.038).

Conclusions

LRG1 may serve as a mediator in the crosstalk between hypoxia and angiogenesis in patients with ADPKD. Additionally, urinary LRG1 levels could potentially reflect disease severity.

Keywords: angiogenesis; autosomal dominant polycystic kidney disease; LRG1

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenetic root of renal failure worldwide. Additionally, it is responsible for ∼10 % of patients with end-stage renal disease in Europe [1]. A series of mutations in a single gene, PKD1 (∼85 %) and PKD2 (∼15 %), which encodes for polycystin 1 (PC1) and 2 (PC2) proteins [2], 3], commonly cause the disease. Multiple clinical symptoms such as hematuria, proteinuria, hypertension, and large kidney size occur in different stages of ADPKD with progressive cyst formation in many organs [4], 5]. The cyst growth process compresses intrarenal vascular structures and causes regional hypoxia and hypoxia-induced angiogenesis in the cystic wall and pericystic tissue [6], 7]. It has been shown that hypoxia increases the secretion of hypoxia-inducible factor-1 alpha (HIF-1α) and several angiogenetic growth factors, including vascular endothelial growth factor (VEGF-A) in cyst epithelial cells [8], 9]. Although a large body of research has shown that HIF-1α and VEGF-A levels are on the increase in patients with ADPKD, the mechanisms underlying hypoxia-induced pathological angiogenesis in ADPKD remain unclear [10], [11], [12]. New mediators involved in crosstalk within dysregulated angiogenesis continue to be discovered.

Leucine-rich α-2-glycoprotein 1 (LRG-1), which is a plasma glycoprotein with a molecular weight of 50 kD, is emerging as a biomarker for pathological angiogenesis, disrupting the cellular interactions necessary for the formation and maintenance of mature vessels [13]. Additionally, it indirectly contributes to the formation of a highly hypoxic and immunosuppressive microenvironment, modulating the TGF-β signaling pathway [14]. Increased plasma LRG-1 levels have been shown in chronic kidney disease (CKD) and diabetic nephropathy alongside kidney transplant recipients [14], [15], [16]. However, there is a lack of research investigating its relationship with ADPKD. Considering abnormal angiogenesis resulting from hypoxia in patients with ADPKD, investigating the role of LRG1 may contribute to elucidating the pathogenesis of ADPKD.

In this study, our ultimate objective is to examine the serum and urine levels of LRG-1 levels in patients with ADPKD at the disease’s various stages with its relationship with VEGF-A and HIF-1α. Additionally, we examined the association of urinary LRG-1 with urine albumin excretion levels in ADPKD.

Materials and methods

Study and control groups

This study included 67 patients with ADPKD attending the nephrology outpatient clinic of Hatay Mustafa Kemal University Hospital and Hitit University Erol Olçok Training and Research Hospital (a two-center study). Twenty-five age- and gender-matched healthy individuals who underwent renal ultrasonography to confirm the absence of ADPKD were included as controls. We divided the patients into two groups based on the estimated glomerular filtration rates (eGFR). ADPKD-I group included 40 patients at an early stage of the disease (stages 1 and 2) who have >60 mL/min/1.73 m2 of eGFR levels. ADPKD-II group included 27 patients at an advanced stage of the disease (stages 3 and 4) who have <60 mL/min/1.73 m2 of eGFR levels). The classification according to eGFR was applied considering the studies in the literature [17], 18]. All demographics and clinical data were obtained from the hospital information system and recorded.

Exclusion criteria

Patients with inflammatory situations, including rheumatological or systemic inflammatory diseases that may affect serum LRG1 levels, patients who had cerebrovascular disease, peripheral vascular disease, hematological disease, hepatic dysfunction, or malignancy, and those with a history of urinary tract infection during the study were not included. In addition, patients with CKD stage 5 or receiving renal replacement therapy due to end-stage renal disease or using drugs including vasopressin receptor antagonists and erythropoietin, as well as pregnant women and pediatric participants, were not recruited within the scope of the research.

Ethical approval

In alignment with the ethical principles for human medical research put forward in the Declaration of Helsinki, consent (informed/written) was acquired from the participants. Also, the Clinical Research Ethics Committee of Hatay Mustafa Kemal University Tayfur Ata Sokmen Medical Faculty granted ethical approval for the study (Decision number/date: 14/01.08.2019).

Sample collection

Fasting blood samples were received from the patient and control groups in 8 mL gel yellow-capped biochemistry tubes (BD Vacutainer SST II Advance). Whole blood samples were collected in 4 mL EDTA-containing tubes (BD Vacutainer® K2 EDTA) and studied on the same day. After centrifugation at 1,500×g for 10 min (refrigerated centrifuge, Thermo Scientific SL 16 R, UK), all serum samples were separated and stored at −80 °C degrees till the study day for ELISA and biochemical analysis. First-morning urine samples (at least 30 mL in a non-sterile urine container) were collected and stored at −80 °C.

Measurement of routine biochemical and ELISA parameters

Serum creatinine, total protein, albumin, spot urine creatinine levels, and serum alanine aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were measured by the spectrophotometric method using an auto-analyzer (Advia 1800, Siemens, Germany). eGFR was analyzed by using the CKD epidemiology collaboration formula (CKD-EPI) [19]. Spot urine albumin levels were measured by the immunoturbidimetric method with the same analyzer (Advia 1800, Siemens, Germany). Complete blood count measurement was performed by an automated whole blood counter device (BC 6800 Mindray, China). Serum VEGF-A (Elabscience, Cat. No: E-EL-H0111), HIF-1α (Elabscience Cat. No.: E-EL-H1277), and serum and urine LRG-1 (Elabscience, Cat. No.: E-EL-H1287) levels were analyzed by using the ELISA method using an ELISA reader (Thermo Scientific/MultiscanGo UV, USA). Urine LRG-1 levels were calculated as µg/100 mg creatinine ratio. The analysis range for LRG-1 is 7.81–500 ng/mL with a sensitivity level of 4.69 ng/mL, intra-assay CV <6.11 %, and inter-assay CV <6.84 %. The analytical range was 31.25–2000 pg/mL, and intra-assay and inter-assay CV values were <5.84 % and <5.19 %, respectively, for serum VEGF-A levels. The analytical range for HIF-1α was 0.16–10 ng/mL with a sensitivity of 0.1 ng/mL and intra-assay and inter-assay CV <6 %.

Magnetic resonance imaging (MRI) protocol and image analysis for total kidney volume (TKV) measurement

Utilizing 32-channel phase-arrayed body coils, 1.5 T MR (Optima MR450w, GE Healthcare, Milwaukee, WI, USA) was used to capture the MRI data. Only unenhanced sequences were included in the imaging protocol. Regarding the views of the field, they were kept at 42 × 42 cm with a 256 × 256 matrix size and a 4 mm slice thickness without an interslice gap. The same radiologist used the manual boundary tracing approach to assess the volumes of both kidneys independently. Kidney borders were manually painted on coronal images, slice by slice. The kidney volume was calculated by automatically summing the volumes for all the slices and multiplying the total area manually drawn for each kidney by the thickness of the slice. To compute TKV, the volumes of the right and left kidneys were added. The hTKV (mL/m) was calculated by an ellipsoid formula using the Mayo Clinic website by entering the requested data for the kidney [20].

Statistical analysis

In our study, the statistical package IBM SPSS Statistics software (SPSS) for Windows, version 21.0 (SPSS Inc., Chicago, IL), and GraphPad Prism 8.4.3 for Windows (GraphPad Software, Boston, MA) were used to analyze patient data. A power analysis for the LRG1 parameter was conducted, resulting in an effect size of f = 0.372 (Cohen’s f), a significance level of α = 0.05, and a statistical power of 80 % (1−β = 0.80). The effect size was determined based on similar studies in the literature and previous pilot data. To assess the differences in means among the three groups, the analysis indicated that a minimum total sample size of 75 would be required. We used the Chi-square test in order to examine the categorical data. Descriptive statistics for categorical data were presented as numbers and percentages. The statistical description of the groups included a number of groups (n), mean ± standard deviation (SD), and median (minimum-maximum) values. The analyses of the Kolmogorov-Smirnov test and the Shapiro-Wilk tests showed normal distribution for the groups. For comparing several independent groups, the research team utilized the ANOVA and Kruskal–Wallis techniques. Post-hoc Tukey or Tamhane’s T2 tests were used to compare groups showing significantly different results in one-way ANOVA. Post-hoc Bonferroni multiple comparison tests were utilized to compare groups showing significant differences in the Kruskal–Wallis test. Pearson and Spearman correlation analyses were employed to investigate the relationships among the parameters. When p<0.05, the significance levels were taken into consideration and marked as statistically significant. A Receiver Operating Characteristic (ROC) analysis was performed using the urinary LRG1 test to differentiate patients in the ADPKD-I group from those with ADPKD-II. The Euclidean distance method was applied to determine the cut-off value on the ROC curve.

Results

The demographic data of all participants are shown in Table 1. Of the 67 patients with ADPKD, female participants were 38 (58 %), while male participants were 29 (42 %). There was no notable difference in terms of gender and body mass index (BMI) for all three groups (Table 1). The median of participants’ ages was 53 years (range: 34–77) in the ADPKD-II group and, as expected, remarkably more than those of the ADPKD-I group (42 years, range: 19–71) (p = 0.002). Both systolic and diastolic blood pressure values were importantly more in both patient groups when comparing with the controls (p<0.001), and hTKV was significantly higher in the ADPKD-II group compared to the ADPKD-I group (p = 0.008). Urinary albumin excretion values were significantly higher, and eGFR values were notably lower within the patient groups compared to the controls. The urinary albumin excretion value was the highest in the ADPKD-II group (p<0.001). Other routine parameters are shown in Table 1. Serum LRG1 levels were notably higher only in the ADPKD-II group compared to the healthy controls (p<0.025); in contrast, the levels in the ADPKD-I group were only marginally significant (p = 0.054) (Figure 1A). Serum HIF-1α and VEGF-A levels were significantly higher in both ADPKD-I and ADPKD-II groups when compared with the healthy controls (p = 0.039, p = 0.029, p<0.001, and p<0.001, respectively) (Figure 1B and C). However, no significant difference was observed for LRG1, HIF-1α, and VEGF-A levels between the ADPKD-I and ADPKD-II groups. Furthermore, urine LRG-1/creatinine values were also remarkably high in both ADPKD-I and ADPKD-II groups compared to the controls, with the highest levels in the ADPKD-II group (p = 0.012, p<0.01) (Figure 1D).

Table 1:

The comparison of demographic, clinical, and biochemical parameters of patients at early and advanced stages of ADPKD and healthy controls.

Parameters Control n = 25 ADPKD-I (stage 1–2) n = 40 ADPKD-II (stage 3–4) n = 27 p-Values
Female/male, na 13/12 26/14 12/15 0.232
Age, yearsa 44 (37–63) 42 (19–71) 53 (34–77) 0.002e
BMI, kg/m2 26.6 ± 3.1 28.5 ± 4.4 28.1 ± 4.3 0.193
Systolic BP, mmHgb 117 ± 11 132 ± 18 136 ± 18 <0.001c,d
Diastolic BP, mmHgb 77 ± 7 85 ± 12 87 ± 12 0.001c,d
hTKV, mL/m NA 619 (211–2323) 1,007 (218–4718) 0.008
HGB, g/dL 13.4 (5.0–16.8) 13.8 (10.7–16.5) 12.5 (9.1–17.1) 0.076
HCT, % 41.0 (33.9–49.3) 41.2 (34.1–48.4) 38.3 (23.6–80.7) 0.285
WBC, 103/µL 6.81 (3.67–9.54) 6.63 (4.02–11.32) 6.20 (3.99–11.80) 0.503
PLT, 103/μLb 244 ± 61 253 ± 56 219 ± 59 0.064
ALT, U/L 19 (7–41) 17 (8–49) 14 (6–86) 0.013d
AST, U/L 20 (9–31) 19 (12–39) 17 (13–56) 0.028d
Total protein, g/dL 6.7 (6.0–7.8) 7.2 (4.3–7.9) 7.1 (5.1–8.6) 0.007c,d
Albumin, g/dL b 4.1 ± 0.4 4.4 ± 0.3 4.3 ± 0.3 0.007c
BUN, mg/dL 13 (7–20) 16 (9–22) 30 (13–73) <0.001d,e
Creatinine, mg/dL 0.69 (0.49–1.03) 0.90 (0.50–1.36) 1.90 (1.10–4.30) <0.001c,d,e
eGFR, mL/min/1.73 m2 109 (73–122) 88 (62–126) 35 (16–57) <0.001c,d,e
Spot urine albumin, mg/g creatinine 7 (2–157) 24 (6–1214) 122 (8–2627) <0.001c,d,e

  1. BP, blood pressure; eGFR, estimated glomerular filtration rate; hTKV, total kidney volume adjusted by height; BMI, body mass index; BUN, blood urea nitrogen; NA, not applied; ADPKD, autosomal dominant polycystic kidney disease. ADPKD-I (stage 1–2), early stage of the disease (eGFR levels >60 mL/min/1.73m2); ADPKD-II (stage 3–4), advanced stage of the disease (eGFR levels <60 mL/min/1.73m2). aChi-square test. bANOVA test, mean ± SD; Kruskal–Wallis test, median (min-max) for other parameters. cControl and ADPKD-I. dControl and ADPKD-II. eADPKD-I and ADPKD-II. A p-value <0.05 was considered statistically significant.

Figure 1: Comparison of serum LRG1 (A), HIF-1α (B), VEGF-A (C), and urine LRG1 (D) levels in the study and control groups. LRG1, leucine-rich α-2-glycoprotein 1; HIF-1α, hypoxia-inducible factor 1-alpha; VEGF-A, vascular endothelial growth factor A; ADPKD, autosomal dominant polycystic kidney disease; eGFR, estimated glomerular filtration rate. ADPKD-I (Stage 1–2), early stage of the disease (eGFR levels >60 mL/min/1.73 m2); ADPKD-II (Stage 3–4), advanced stage of the disease (eGFR levels <60 mL/min/1.73 m2). A p-value<0.05 was considered statistically significant.
Figure 1:

Comparison of serum LRG1 (A), HIF-1α (B), VEGF-A (C), and urine LRG1 (D) levels in the study and control groups. LRG1, leucine-rich α-2-glycoprotein 1; HIF-1α, hypoxia-inducible factor 1-alpha; VEGF-A, vascular endothelial growth factor A; ADPKD, autosomal dominant polycystic kidney disease; eGFR, estimated glomerular filtration rate. ADPKD-I (Stage 1–2), early stage of the disease (eGFR levels >60 mL/min/1.73 m2); ADPKD-II (Stage 3–4), advanced stage of the disease (eGFR levels <60 mL/min/1.73 m2). A p-value<0.05 was considered statistically significant.

In the ADPKD-I group, a notable positive correlation was observed between hTKV and systolic and diastolic blood pressures (r = 0.491, r = 0.502, p = 0.001). However, it was reported as being negatively correlated with eGFR values (r = −0.559, p<0.001) (Figure 2A). Urine LRG1/creatinine ratios were positively correlated with urine albumin/creatinine ratios (r = 0.338, p = 0.038) (Figure 2B). In the ROC analysis, the cut-off value for urinary LRG1 was identified as 2.28 μg/g creatinine. The sensitivity corresponding to this cut-off was found to be 89 %, and the specificity was 50 % (Figure 3).

Figure 2: The correlations of eGFR and hTKV (A) and urine LRG1/creatinine and albumin/creatinine levels (B) in patients in the ADPKD-I group. eGFR, estimated glomerular filtration rate; hTKV, total kidney volume adjusted by height; LRG1, leucine-rich α-2-glycoprotein 1; ADPKD, autosomal dominant polycystic kidney disease. The correlations were assessed using the Pearson correlation test. A p-value<0.05 was considered statistically significant.
Figure 2:

The correlations of eGFR and hTKV (A) and urine LRG1/creatinine and albumin/creatinine levels (B) in patients in the ADPKD-I group. eGFR, estimated glomerular filtration rate; hTKV, total kidney volume adjusted by height; LRG1, leucine-rich α-2-glycoprotein 1; ADPKD, autosomal dominant polycystic kidney disease. The correlations were assessed using the Pearson correlation test. A p-value<0.05 was considered statistically significant.

Figure 3: Receiver operating characteristic (ROC) analysis for the urinary LRG1 test. AUC, area under the curve; CI, confidence interval; ADPKD, autosomal dominant polycystic kidney disease; LRG1, leucine-rich α-2-glycoprotein-1; Cre, creatinine. A p-value <0.05 was considered statistically significant.
Figure 3:

Receiver operating characteristic (ROC) analysis for the urinary LRG1 test. AUC, area under the curve; CI, confidence interval; ADPKD, autosomal dominant polycystic kidney disease; LRG1, leucine-rich α-2-glycoprotein-1; Cre, creatinine. A p-value <0.05 was considered statistically significant.

In the ADPKD-II group, serum HIF-1α positively correlated with VEGF-A (r = 0.400, p = 0.038). However, no significant correlations were observed for other parameters in the ADPKD-II group (p>0.05).

Discussion

The objective of this research was to examine the linkage between LRG1 and proangiogenic factors in patients of ADPKD at various stages of renal function. The results of the study depicted significantly higher serum LRG1 levels only in the patients at an advanced stage (ADPKD-II, stage 3–4) compared to the healthy control group. Serum HIF-1α and VEGF-A levels were noticeably higher in both patient groups compared to the healthy controls, but no important difference was observed between patients who are at the early and advanced stages of the disease. Besides, HIF-1α and VEGF-A levels were significantly correlated only in patients at the advanced stage. Urinary LRG-1/creatinine ratios were also significantly higher in both patient groups compared to the controls but highest in the patients at the advanced stage. Additionally, urinary LRG-1 excretion levels were remarkably and positively correlated with urinary albumin levels in the patients at the early stage, but no correlation was found in the patients at the advanced stage.

Although the precise pathogenesis of ADPKD remains incompletely understood, accumulating evidence from previous studies implicates the involvement of hypoxia-induced angiogenesis in the disease process [6]. LRG1 has emerged as a novel mediator for abnormal angiogenesis and has been identified as a potential biomarker in kidney diseases [16], 21]. However, no study has been conducted on patients with ADPKD. We found significantly higher levels of circulating LRG1 levels only in the ADPKD-II group compared to the healthy controls (Figure 1A) (p = 0.025). An increase was observed in the ADPKD-I group; however, this increase did not reach statistically significant levels (p = 0.054). Additionally, hTKV values were also significantly higher in the ADPKD-II group (p = 0.008) (Table 1) and correlated negatively with eGFR values, as expected (r = −0.559, p<0.001) (Figure 2A). However, we could not find any association between LRG1 levels, hTKV, and eGFR in patient groups. Prior experimental studies put forward a significant angiogenic activity supporting a rich vascular network covering the enlarged cysts in ADPKD [22]. Also, others reported higher levels of proangiogenic mediators in ADPKD, confirming the link between hypoxia and angiogenesis in the disease pathogenesis [10], 23]. LRG1, as an angiogenic mediator, exerts its effect by promoting endothelial cell proliferation, migration, and tubulogenesis [13]. In this study, noticeably higher levels of LRG1 may be a reflection of abnormal angiogenesis due to more expanded cystic formation in the advanced stage of ADPKD. The association of LRG1 and pathological angiogenesis has been studied previously in animal models and various disease conditions, including colorectal cancer and diabetic nephropathy [15], 21], 24]. They suggested that LRG1 mediates its influences by modulating the TGF-β signaling pathway and raising the secretion of pro-angiogenic factors such as VEGF-A and HIF-1α. Furthermore, LRG1 has been shown to promote ocular neovascularization in diabetic retinopathy and direct glomerular endothelial cells into a pro-angiogenic pathway [15], 24]. Therefore, it is suggested that LRG1 may serve as a pivotal mediator in the interplay between hypoxic and angiogenetic mediators. In the current study, similar to serum LRG1 levels, we also found increased serum HIF-1α and VEGF-A levels in the ADPKD-II group compared to the controls (p<0.001) (Figure 1B and C). Our results were consistent with the study conducted by Raptis et al. In their study, they reported higher serum HIF-1α levels together with angiogenetic markers in an advanced stage of ADPKD compared to both mild cases and controls [25]. Furthermore, serum HIF-1α and VEGF-A levels (r = 0.400, p = 0.038) were found to be positively correlated only in the ADPKD-II group (p<0.001). VEGF-A is activated by HIF-1α in hypoxic environments and is linked to pathological angiogenesis in a number of disorders [26], 27]. Some studies involving animal models and ADPKD patients indicate that VEGF-A signaling may promote increased proliferation of epithelial cells, directly fostering cyst expansion [9], 28]. Therefore, increased LRG1, HIF-1α, and VEGF-A levels in the ADPKD-II group can be attributed to severe hypoxia, which is an expected phenomenon due to the enlarged cystic formation at the advanced stage of the disease. We may suggest that LRG1 may activate the pro-angiogenic pathway in patients with ADPKD and contribute microcirculatory changes with mechanisms similar to those suggested in the studies mentioned above.

However, there was no significant change observed for serum LRG1, HIF-1α, and VEGF-A levels between the ADPKD-I and ADPKD-II groups. On the other hand, circulating levels of HIF-1α and VEGF-A notably increased in the ADPKD-I group compared to the healthy controls. (p = 0.039, p<0.001) (Figure 1B and C). It seems that HIF-1α and VEGF-A may appear earlier in the course of ADPKD and trigger the disease progression, unlike LRG1. Yet no important correlation was reached between these parameters and hTKV or eGFR levels in any stage of the disease. Therefore, further studies recruiting a large number of patients are required to examine the possibility of the relationships between the parameters and disease severity.

In addition, we found significantly increased levels of urinary LRG1 and albumin excretions in both patient groups compared to the controls (Figure 1D, Table 1), with the highest levels observed in the ADPKD-II group (p<0.001). Interestingly, urinary LRG1/creatinine levels were significantly correlated with urinary albumin/creatinine levels only in the ADPKD-I group (r = 0.338, p = 0.038) (Figure 2B). In the advanced stages of the disease, an increase in urinary protein excretion is an expected finding and reflects renal damage [29]. In a previous study, higher levels of serum and urine LRG-1 levels were reported to be affiliated with injuries arising from kidney transplantation and the worsening of functions [16]. LRG1 and proteinuria were found to correlate positively in patients with kidney transplantation. Additionally, elevated levels of LRG1 were traced in the mice’s urine after renal injury, indicating higher production by renal tubular epithelial cells [30]. It has also been suggested that high levels of LRG-1 may cause structural and/or functional abnormalities in glomerular endothelial cells, leading to deterioration in the barrier of filtration, albuminuria, and a decrease in the rate of filtration in patients with diabetes [15]. We also performed ROC analysis between the early and advanced stages of the disease, and we identified a cut-off value of 2.28 μg/g creatinine for urinary LRG1. The sensitivity at this cut-off was 89 %, while the specificity was 50 % (Figure 3). It can be speculated that urinary LRG1 excretion levels can be related to disease severity and a better indicator for patients with early stages of ADPKD compared to its serum levels, though the low specificity highlights the need for additional diagnostic tools to improve accuracy.

Although this study has many strengths, it also suffers from a few limitations that need to be taken into account. Firstly, the size of the sample was relatively small. Though this is a preliminary study, a larger sample would increase the statistical rigor of the study. Secondly, the inability to determine which specific mutations in patients may affect disease progression. Therefore, the relationship between these mutations and LRG-1, VEGF-A, and HIF-1α could not be evaluated. Thirdly, we were unable to regulate the possible confounding impacts of additional variables, including the utilization of medications and the existence of comorbid conditions. Despite these limitations, the study provides valuable findings in the pathophysiological process of ADPKD.

In conclusion, LRG1 may play a role in relation to VEGF-A and HIF-1α in the abnormal angiogenesis observed in patients with ADPKD. Additionally, we suggest that urinary LRG1 excretion levels can be a potentially promising candidate as a biochemical marker for disease severity in patients with ADPKD.

Corresponding author: Oguzhan Ozcan, Department of Biochemistry, Faculty of Medicine, Hatay Mustafa Kemal University, Serinyol, 31100, Hatay, Türkiye, E-mail:

Funding source: Hatay Mustafa Kemal University Scientific Research Projects Coordination

  1. Research ethics: Ethical approval was obtained by the Clinical Research Ethics Committee of Hatay Mustafa Kemal University Tayfur Ata Sokmen Medical Faculty (Decision number/date, 14/01.08.2019).

  2. Informed consent: Informed consent was obtained from all participiants included in the study in accordance with the Declaration of Helsinki Ethical Principles for Human Medical Research.

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: Authors state no conflict of interest.

  6. Research funding: Our Research was funded by Hatay Mustafa Kemal University Scientific Research Projects Coordination.

  7. Data availability: Not applicable.

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Received: 2024-07-24
Accepted: 2024-12-09
Published Online: 2025-03-20

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/tjb-2024-0266
Keywords for this article
angiogenesis; autosomal dominant polycystic kidney disease; LRG1
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Interaction of fetuin-A with obesity related insulin resistance and diabetes mellitus
  4. Research Articles
  5. Preanalytical errors in pediatric blood sampling: a systematic review of common challenges and risks
  6. The promotive role of reticulocalbin 3 (RCN3) in the pathogenesis of keloid via TGFβ1/Smad2/Smad7 signaling pathway in vitro
  7. Investigation into drug resistance to cisplatin in cancer stem cell-enriched population in non-small cell lung cancer
  8. The cytotoxic and antiproliferative effect of Polygala saponin XLIV on the human colorectal carcinoma cell line
  9. Development of HEK293T cell reference materials for β-thalassemia genetic testing using prime editing
  10. Investigation of propofol, fentanyl, and midazolam-related toxicity and the protective effect of midazolam on THLE-2 cell lines
  11. Leucine-rich α-2-glycoprotein 1 can be a novel angiogenic mediator in autosomal dominant polycystic kidney disease
  12. Asiaticoside reverses the inhibition effect of miR-184 on proliferation, migration and AKT phosphorylation of HTR-8/Svneo cells
  13. Perioperative D-dimer levels and head and neck cancer surgery: a prospective observational study
  14. Comprehensive analysis of KRT15 in pan-cancer and verification in lung adenocarcinoma
  15. Age and sex-dependent effects of nitrosative stress on the osmotic fragility of human red blood cells
  16. Evaluation of oxidative stress parameters in older patients with urinary incontinence
  17. Determination of reference change values for thyroid-related biomarkers: TSH, fT3, fT4, Tg, Anti-Tg, and Anti-TPO
  18. An evaluation of serum boron level in pregnancies with severe pre-eclampsia
  19. Involvement of SIRT3/FOXO1 and TLR4/NF-κB/NLRP3 pathways in protective effects of Δ(9)-tetrahydrocannabinol on diabetic cardiomyopathy in rats
  20. Evaluating the potential therapeutic effect of Rosa damascena Mill. essential oil on acetic acid-induced ulcerative colitis in rats
  21. Assessment of blood collection competency in phlebotomists: a survey study
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