Introduction: The present study investigated the role of long non-coding RNA (lncRNA) GABPB1-IT1 in ischemia-induced acute kidney injury (AKI). Methods: The expression of GABPB1-IT1 in the plasma of patients with ischemia-induced AKI and healthy controls was detected by RT-qPCR. GABPB1-IT1 and miR-204-5p were overexpressed in human renal proximal tubular epithelial cells (HRPTEpCs), followed by RT-qPCR to assess the overexpression effect and the regulatory relationship between GABPB1-IT1 and miR-204-5p. Methylation-specific PCR was performed to assess the promoter methylation status of miR-204-5p. Additionally, a cell apoptosis assay was carried out to evaluate the correlation between miR-204-5p and GABPB1-IT1 in the context of hypoxia-induced apoptosis of HRPTEpCs. Results: GABPB1-IT1 was upregulated in the plasma of patients with ischemia-induced AKI. In HRPTEpCs, hypoxia upregulated the expression of GABPB1-IT1. MiR-204-5p was downregulated in ischemia-induced AKI, and the expression of miR-204-5p was inversely correlated with GABPB1-IT1. In HRPTEpCs, overexpression of GABPB1-IT1 decreased the expression levels of miR-204-5p and increased miR-204-5p gene methylation. In addition, overexpression of GABPB1-IT1 reduced the inhibitory effects of miR-204-5p on the apoptosis of HRPTEpC induced by hypoxia. Furthermore, overexpression of GABPB1-IT1 promoted kidney injury, renal tissue injury scores, and the level of serum creatinine. However, miR-204-5p had the opposite effect. Conclusion: GABPB1-IT1 was upregulated in ischemia-induced AKI and may induce hypoxia-induced apoptosis of HRPTEpC by methylation of miR-204-5p.

Obstruction or functional constriction of a blood vessel could cause reduced blood and oxygen supply to major organs of the human body, such as the kidney, leading to the development of renal ischemia [1, 2], which is a major cause of acute kidney injury (AKI) that has a high rate of mortality and morbidity [3, 4]. Ischemia-induced AKI causes multiple pathological changes, such as the loss and effacement of the proximal tubule brush border and damage to the tubule cells [5]. Without immediate and proper treatment, these pathological changes can progress irreversible, leading to the development of chronic renal disorders such as long-term kidney failure and chronic kidney disease. In severe instances, dialysis becomes imperative [6, 7].

Previous studies have identified several molecular pathways involved in ischemia-induced AKI [8, 9]. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in ischemia-induced AKI [10]. A recent study reported that miR-204-5p was involved in an ischemia-induced AKI mice model [11]. Through Bioinformatics analysis and Luciferase experiment (online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000539342), we discovered no direct interaction between GABPB1 and miR-204-5p. However, it was observed that GABPB1 could downregulate miR-204-5p. Therefore, this study was conducted to explore the roles of GABPB1-IT1 and miR-204-5p in ischemia-induced AKI.

Study Subjects and Plasma Preparation

This study enrolled a total of 60 patients with ischemia-induced AKI (24 females and 36 males, age range from 30 to 63 years old, with a mean age of 46.4 ± 7.8 years old) and 60 healthy controls (24 females and 36 males, age range from 30 to 63 years old, with a mean age of 46.6 ± 7.9 years old) (Table 1) who were admitted at Brain Hospital of Hunan Province (the Second People’s Hospital of Hunan Province) between March 2016 and March 2019. All patients enrolled in this study had no prior history of AKI and had not received any prior therapy. Exclusion criteria included pregnant individuals, organ transplant recipients, as well as those with a history of bone marrow transplantation, corticosteroid use, or acquired immune deficiency syndrome. The physiological functions of all healthy controls were normal. Blood samples (5 mL) were collected from all participants and mixed with EDTA, followed by centrifugation (1,200 g) at room temperature for 10 min to obtain plasma samples. The plasma samples were then stored in liquid nitrogen. Similar results were found in urine samples (online suppl. Fig. 2). The Ethics Committee of the aforementioned hospital approved this study. All participants signed the informed consent.

Table 1.

Clinical parameters of the study subjects

Clinical parametersH/R (n = 60)Healthy subjects (n = 60)p value
Sex (male/female) 30/30 30/30 1.000 
Age, years 32.1±6.7 22.0±6.8 0.773 
Tobacco 68.3% (41) 50% (30) 0.091 
Hypertension 76% (46) ≠ 
Diabetes mellitus 18% (11) ≠ 
Body mass index, kg/m2 21±1.2 20±1.8 0.000 
Glucose, mmol/L 3.1±1.1 3.5±0.2 0.000 
BUN, mg/dLa 42.16±19.54 13.25±2.59 0.004 
Serum creatininea 5.85±1.54 0.35±0.05 0.001 
Cerebrovascular disease 0.500 
Clinical parametersH/R (n = 60)Healthy subjects (n = 60)p value
Sex (male/female) 30/30 30/30 1.000 
Age, years 32.1±6.7 22.0±6.8 0.773 
Tobacco 68.3% (41) 50% (30) 0.091 
Hypertension 76% (46) ≠ 
Diabetes mellitus 18% (11) ≠ 
Body mass index, kg/m2 21±1.2 20±1.8 0.000 
Glucose, mmol/L 3.1±1.1 3.5±0.2 0.000 
BUN, mg/dLa 42.16±19.54 13.25±2.59 0.004 
Serum creatininea 5.85±1.54 0.35±0.05 0.001 
Cerebrovascular disease 0.500 

Pearson’s χ2 was used for statistical analysis.

ap < 0.05 was considered statistically significant.

Cell Culture

Human renal proximal tubular epithelial cells (HRPTEpCs; Sigma-Aldrich, USA) were used for cell experiments. The cell culture medium consisted of 90% renaEpi growth medium and 10% FBS. Cell culture conditions were maintained at 37°C, 95% humidity and 5% CO2.

Cell Transfections

The GABPB1-IT1 expression vector was constructed using the pcDNA3.1 vector (Sigma-Aldrich) as the backbone. HRPTEpCs were transfected with either miR-204-5p mimic (Sigma-Aldrich, 40 nm) or the GABPB1-IT1 expression vector (10 nm) using lipofectamine 2000 (Invitrogen). In the co-transfection group (Co group), cells were simultaneously transfected with both miRNA and the expression vector. Untransfected cells were used as the Control (C), while cells transfected with either NC miRNA or an empty pcDNA3.1 vector were designated as NC.

RT-qPCR Assays

RNAs isolation was performed on plasma and HRPTEpCs using Ribozol (Sigma-Aldrich). For hypoxia treatment, HRPTEpCs were cultured under hypoxia conditions (5% CO2/94% N2/1% O2) for 12, 24 and 48 h prior to use. Subsequently, RNA was precipitated using 85% ethanol. Genomic DNA was eliminated by treating RNA samples with DNase I (Sigma-Aldrich) at 37°C for 2 h. RNA concentrations were measured using a NanoDrop 2000 Spectrophotometer (Thermo Scientific). qPCR assays were conducted using the Precision nanoScript2 Reverse Transcription Kit (PrimerDesign) and SYBR Green PCR Kit (Takara Bio). GAPDH was used as the endogenous control. All-in-One™ miRNA qRT-PCR Detection Kit (Genecopoeia) was used to detect the expression of mature miR-204-5p. Gene expression was normalized using the 2−ΔΔCt method. PCR reactions were replicated for 3 times.

Methylation-Specific PCR

At 48 h post-transfection, genomic DNAs were extracted from HRPTEpCs using the genomic DNA Extraction Kit (ab156900, Abcam). DNA concentrations were quantified using the NanoDrop 2000 Spectrophotometer. The EZ DNA Methylation-Gold™ kit (ZYMO RESEARCH) was used to convert genomic DNA. The promoter of miR-204-5p methylation was assessed using the Taq DNA polymerase kit (NEB). The un-methylated primer was 162 bp in length with a melting temperature (Tm) of 65.8°C. The forward methylated primer was 100 bp in length with a Tm of 65°C. The primer sequences were as follows: Forward un-methylated primer, 5′-TGT​GTT​GGA​GGT​TAG​GTT​TTA​AAG​T-3′; Reverse un-methylated primer, 5′-CAA​AAA​TTA​CCC​AAT​ACC​CCA​TAT​A-3′; Forward methylated primer, 5′-TTG​GAG​GTT​AGG​TTT​TAA​AGT​TGC-3′; Reverse methylated primer, 5′-AAA​TTC​TTC​ATT​CTT​CTA​CCT​ACG​AT-3′.

Cell Apoptosis Assay

HRPTEpCs cells were collected to evaluate cell apoptosis at 48 h post-transfection. In each experimental group, including the C group, NC groups, GABPB1-IT1 group, miR-204-5p group and Co group (as described in the Cell Transfections section), cells were cultured under hypoxia conditions (5% CO2/94% N2/1% O2) for an additional 48 h. Subsequently, cells were stained with FITC Annexin V (Sigma-Aldrich) and propidium iodide (PI) for 20 min in the dark. Finally, apoptotic cells were sorted using flow cytometry.

Establishment of AKI Mode

Male C57BL/6J mice (age 10–12 weeks old) were intraperitoneally injected with pentobarbital sodium (30 mg/kg body weight) for anesthesia. Once anesthetized, the mice were positioned supine on the operating board, and the abdominal surgical area was meticulously disinfected and shaved. A heating plate was used to maintain body temperature throughout the surgical procedure. A median abdominal incision was carefully made, and the bilateral renal capsule was gently separated. Subsequently, the bilateral renal arteries were temporarily occluded using a non-invasive artery clamp for 60 min to induce ischemia. Following this period, the clamp was released to restore renal perfusion, thus establishing the AKI model.

Hematoxylin and Eosin Staining

Kidney sections (5 μm) were dewaxed and rehydrated, followed by staining with Mayer’s hematoxylin solution for 30 s and 1% eosin Y solution for an additional 30 s. Then the slides were dehydrated and mounted for photo capturing. Hematoxylin (#MHS1) and eosin solution (#1170811000) were purchased from Sigma-Aldrich (St. Louis, USA). Epithelial cell swelling, epithelial interstitial edema, renal tubular ectasia and tubule damage were identified in the sections and compared across different groups.

ELISA Assay

The level of serum creatinine was detected using the ELISA kit (Beyotime, Shanghai, China) following the manufacturer’s instructions.

Immunohistochemistry

The collected tissues were deparaffinized, followed by blocking with 3% H2O2 for 15 min after dewaxing and hydration. Next, the samples were incubated with 5% bovine serum albumin for 45 min to minimize nonspecific binding. Primary antibodies (anti-caspase-3, ab13847, 1:200, Abcam) were then applied and allowed to incubate with the samples at 4°C for 12 h. Following PBS washing, secondary goat anti-rabbit lgG (ZSGB-Bio, Beijing, China) was added for incubation at 37°C for 60 min. The DAB chromogen kit (ZSGB-BIO, Beijing, China) was used to stop the immunohistochemistry staining. A fluorescence microscope (Nikon, Japan) was used to capture images. The Image J software was used for the analysis of immunohistochemistry images.

Statistical Analyses

Data were shown as the mean ± SEM values of 3 biological replicates. Unpaired t test and Kruskal-Wallis H test was used to compare differences between two groups or among multiple groups, respectively. Correlations between characteristics with continuous distributions were assessed using Spearman’s rank correlation coefficient (ρ). Pearson’s χ2 correlation coefficient was used for categorical variables. p < 0.05 was considered as statistically significant.

GABPB1-IT1 Was Upregulated in Ischemia-Induced AKI

The expression of GABPB1-IT1 in plasma from patients with ischemia-induced AKI (n = 60) and healthy controls (n = 60) were evaluated. It was observed that the expression levels of GABPB1-IT1 were significantly higher in ischemia-induced AKI patients in comparison with that in the healthy controls (Fig. 1a, p < 0.05). In addition, HRPTEpCs were cultivated under hypoxia conditions for 12, 24 and 48 h, followed by measuring the expression of GABPB1-IT1. It was observed that hypoxia treatment increased the expression levels of GABPB1-IT1 in a time-dependent manner (Fig. 1b, p < 0.05).

Fig. 1.

GABPB1-IT1 was upregulated in ischemia-induced AKI. a Levels of GABPB1-IT1 in plasma from patients with ischemia-induced AKI (n = 60) and healthy controls (n = 60) were measured by RT-qPCR. b HRPTEpCs were cultivated under hypoxia conditions (1% O2/94% N2/5% CO2) for 12, 24 and 48 h, followed by the measurement of GABPB1-IT1 expression by RT-qPCR. All experiments were repeated 3 times and mean values were presented. *p < 0.05.

Fig. 1.

GABPB1-IT1 was upregulated in ischemia-induced AKI. a Levels of GABPB1-IT1 in plasma from patients with ischemia-induced AKI (n = 60) and healthy controls (n = 60) were measured by RT-qPCR. b HRPTEpCs were cultivated under hypoxia conditions (1% O2/94% N2/5% CO2) for 12, 24 and 48 h, followed by the measurement of GABPB1-IT1 expression by RT-qPCR. All experiments were repeated 3 times and mean values were presented. *p < 0.05.

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MiR-204-5p Was Downregulated in Ischemia-Induced AKI

MiR-204-5p expression in plasma from patients with ischemia-induced AKI (n = 60) and healthy controls (n = 60) were also evaluated. It was observed that the expression levels of miR-204-5p were significantly lower in ischemia-induced AKI patients in comparison with that in the healthy controls (Fig. 2a, p < 0.05). Correlations between the expression of miR-204-5p and GABPB1-IT1 were analyzed, and it was observed that they were inversely correlated across ischemia-induced AKI patients (Fig. 2b) and healthy controls (Fig. 2c).

Fig. 2.

MiR-204-5p was downregulated in ischemia-induced AKI and inversely correlated with GABPB1-IT1. Levels of miR-204-5p in plasma from patients with ischemia-induced AKI (n = 60) and healthy controls (n = 60) were also measured by performing RT-qPCR. a PCR reactions were repeated 3 times and mean values were presented. *p < 0.05. Correlations between plasma levels of miR-204-5p and GABPB1-IT1 across plasma sample from both ischemia-induced AKI patients (b) and healthy controls (c) were analyzed by Spearman’s correlation coefficient.

Fig. 2.

MiR-204-5p was downregulated in ischemia-induced AKI and inversely correlated with GABPB1-IT1. Levels of miR-204-5p in plasma from patients with ischemia-induced AKI (n = 60) and healthy controls (n = 60) were also measured by performing RT-qPCR. a PCR reactions were repeated 3 times and mean values were presented. *p < 0.05. Correlations between plasma levels of miR-204-5p and GABPB1-IT1 across plasma sample from both ischemia-induced AKI patients (b) and healthy controls (c) were analyzed by Spearman’s correlation coefficient.

Close modal

Overexpression of GABPB1-IT1 Increased miR-204-5p Gene Methylation in HRPTEpCs

Transfection of miR-204-5p mimic and GABPB1-IT1 expression vector into HRPTEpCs confirmed the efficacy of overexpression (Fig. 3a, p < 0.05). Compared to the NC and C group, overexpression of GABPB1-IT1 led to decreased expression levels of miR-204-5p (Fig. 3b, p < 0.05), while overexpression of miR-204-5p did not affect the expression of GABPB1-IT1 (Fig. 3c). In addition, HRPTEpCs transfected with GABPB1-IT1 expression vector exhibited increased miR-204-5p gene methylation compared to those transfected with an empty pcDNA 3.1 vector (Fig. 3d). Moreover, co-transfection of the GABPB1-IT1 expression vector and miR-204-5p mimic (Co) upregulated GABPB1-IT1 expression but had no impact on the expression of miR-204-5p (Fig. 3e, p < 0.05). Methylation-specific PCR showed that miR-204-5p gene methylation was also increased in the Co group (Fig. 3f).

Fig. 3.

a Overexpression of GABPB1-IT1 led to downregulation of miR-204-5p and increased methylation of miR-204-5p gene in HRPTEpCs. HRPTEpCs were transfected with GABPB1-IT1 expression vector or miR-204-5p mimic, followed by the confirmation of GABPB1-IT1 and miR-204-5p overexpression by RT-qPCR. The effects of GABPB1-IT1 overexpression on miR-204-5p (b) and the effects of miR-204-5p overexpression on GABPB1-IT1 (c) were also analyzed by RT-qPCR. MSP was performed to analyze the effects of overexpression of GABPB1-IT1 on the methylation of miR-204-5p (d). In addition, co-transfection of GABPB1-IT1 expression vector and miR-204-5p mimic (Co) was also performed, and the effects of Co on GABPB1-IT1 and miR-204-5p expression (e) and miR-204-5p gene methylation (f) were analyzed by RT-qPCR and MSP, respectively. All experiments were repeated 3 times and mean values were presented. MSP, methylation-specific PCR. *p < 0.05.

Fig. 3.

a Overexpression of GABPB1-IT1 led to downregulation of miR-204-5p and increased methylation of miR-204-5p gene in HRPTEpCs. HRPTEpCs were transfected with GABPB1-IT1 expression vector or miR-204-5p mimic, followed by the confirmation of GABPB1-IT1 and miR-204-5p overexpression by RT-qPCR. The effects of GABPB1-IT1 overexpression on miR-204-5p (b) and the effects of miR-204-5p overexpression on GABPB1-IT1 (c) were also analyzed by RT-qPCR. MSP was performed to analyze the effects of overexpression of GABPB1-IT1 on the methylation of miR-204-5p (d). In addition, co-transfection of GABPB1-IT1 expression vector and miR-204-5p mimic (Co) was also performed, and the effects of Co on GABPB1-IT1 and miR-204-5p expression (e) and miR-204-5p gene methylation (f) were analyzed by RT-qPCR and MSP, respectively. All experiments were repeated 3 times and mean values were presented. MSP, methylation-specific PCR. *p < 0.05.

Close modal

GABPB1-IT1 Promoted Apoptosis Induced by Hypoxia through miR-204-5p in HRPTEpCs

Comparison with the C group revealed that overexpression of miR-204-5p led to a reduction in cell apoptotic rate (Fig. 4, p < 0.05). In contrast, overexpression of GABPB1-IT1 increased cell apoptotic rate and attenuated the inhibitory effects of miR-204-5p overexpression on HRPTEpC apoptosis (p < 0.05). Moreover, an AKI model was established in rats, and immunohistochemistry staining was used to detect the expression of caspase-3. Compared to the healthy controls, the model group exhibited a more pronounced positive reaction of cas-3, indicative of increased apoptosis (Fig. 5a, p < 0.05). Additionally, overexpression of GABPB1-IT1 increased the expression levels of cas-3, which were reversed by miR-204-5p (p < 0.05). Hematoxylin and eosin staining and ELISA assay revealed that overexpression of GABPB1-IT1 resulted in epithelial cell swelling, interstitial edema, renal tubular ectasia, and tubule damage in mouse kidney tissues (Fig. 5b). Consequently, renal tissue injury scores were significantly increased following GABPB1-IT1 treatment (p < 0.05). Moreover, overexpression of GABPB1-IT1 drastically increased the plasma level of serum creatinine in mice (Fig. 5c, p < 0.05). In contrast, overexpression of miR-204-5p relieved kidney injury and decreased renal tissue injury scores. Furthermore, overexpression of miR-204-5p significantly inhibited the plasma level of serum creatinine in mice. However, these protective effects of miR-204-5p were abolished by overexpression of GABPB1-IT1.

Fig. 4.

GABPB1-IT1 promoted the apoptosis of HRPTEpCs induced by hypoxia through miR-204-5p. The roles of GABPB1-IT1 and miR-204-5p in regulating the apoptosis of HRPTEpCs induced by hypoxia were analyzed by performing cell apoptosis analysis. All experiments were repeated 3 times and mean values were presented. *p < 0.05.

Fig. 4.

GABPB1-IT1 promoted the apoptosis of HRPTEpCs induced by hypoxia through miR-204-5p. The roles of GABPB1-IT1 and miR-204-5p in regulating the apoptosis of HRPTEpCs induced by hypoxia were analyzed by performing cell apoptosis analysis. All experiments were repeated 3 times and mean values were presented. *p < 0.05.

Close modal
Fig. 5.

GABPB1-IT1 promoted the apoptosis of HRPTEpCs induced by hypoxia through miR-204-5p in vivo. a The role of GABPB1-IT1 and miR-204-5p in regulating the apoptosis of HRPTEpCs induced by hypoxia in vivo were analyzed by Immunohistochemistry. b H&E staining was performed to evaluate kidney injury. Tubular injury score was detected in renal tissues. c Serum creatinine was detected by ELISA assay. All experiments were repeated 3 times and mean values were presented. H&E, hematoxylin and eosin. *p < 0.05.

Fig. 5.

GABPB1-IT1 promoted the apoptosis of HRPTEpCs induced by hypoxia through miR-204-5p in vivo. a The role of GABPB1-IT1 and miR-204-5p in regulating the apoptosis of HRPTEpCs induced by hypoxia in vivo were analyzed by Immunohistochemistry. b H&E staining was performed to evaluate kidney injury. Tubular injury score was detected in renal tissues. c Serum creatinine was detected by ELISA assay. All experiments were repeated 3 times and mean values were presented. H&E, hematoxylin and eosin. *p < 0.05.

Close modal

In the present study, we observed that GABPB1-IT1 was upregulated in ischemia-induced AKI and could downregulate the expression of miR-204-5p by increasing miR-204-5p gene methylation to promote HRPTEpC apoptosis induced by hypoxia. GABPB1-IT1 has been previously identified as downregulated in non-small cell lung cancer and associated with poor survival outcomes in non-small cell lung cancer patients [12]. However, its involvement in other diseases and its role in regulating physiological and pathological processes remain unclear. This study reported the upregulation of GABPB1-IT1 in ischemia-induced AKI and HRPTEpCs, where it was found to promote HRPTEpC apoptosis under hypoxia conditions. Therefore, it suggests that hypoxia-induced GABPB1-IT1 expression may contribute to cell apoptosis. However, the molecular mechanisms underlying the regulation of GABPB1-IT1 by hypoxia remain elusive.

MiR-204-5p has been shown to participate in multiple renal disorders [13, 14]. For instance, miR-204-5p targets IL-6R to suppress chemokine generation and IL-6-mediated inflammatory response in HK-2 cells [14]. Another study revealed that altered expression of miR-204-5p could be a sensitive biomarker for renal cell carcinoma [13]. MiR-204-5p is downregulated in mice model of ischemia-induced renal injury and it targets the Fas/FasL pathway to suppress disease progression [11]. In line with these findings, miR-204-5p was found to be downregulated in plasma of patients with ischemia-induced AKI in our study. Moreover, we demonstrated that overexpression of miR-204-5p could suppress HRPTEpC apoptosis induced by hypoxia, both in vitro and in vivo. It is worth noting that loss and effacement of proximal tubule brush border are commonly observed in AKI patients [5]. Therefore, the overexpression of miR-204-5p might be used as a potential therapeutic strategy to mitigate the pathological changes associated with AKI.

It is well-established that miRNAs can be regulated by lncRNAs through methylation pathways [15]. In this study, GABPB1-IT1 was identified as a regulator of miR-204-5p downregulation via methylation mechanisms. However, it is important to acknowledge the limitations of the present study, primarily the small sample size. Future investigations should aim to enroll a larger cohort of patients and conduct a more comprehensive evaluation of the AKI animal model. In conclusion, our findings suggest that GABPB1-IT1 is upregulated in ischemia-induced AKI and may mitigate HRPTEpC apoptosis induced by hypoxia through the regulation of miR-204-5p methylation.

This study protocol was reviewed and approved by the Ethics Committee of Brain Hospital of Hunan Province, with approval No. 1614. Written informed consent was obtained from all individual patients included in the study.

The authors declare that they have no competing interests.

This study did not receive any funding.

F.F. conducted this study and wrote this manuscript. F.F. and R.Z. analyzed and interpreted the patient data. L.L. designed the study. All authors read and approved the final manuscript.

Additional Information

Fang Feng and Ru Zhang contributed equally to this work.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request. All original figures were provided in the supplementary files named “original figures.docx”.

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