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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

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Front. Med.    2020, Vol. 14 Issue (3) : 293-304    https://doi.org/10.1007/s11684-019-0715-7
RESEARCH ARTICLE
Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease
Xiaojing Jiao1,2, Dong Zhang1, Quan Hong1, Lei Yan2, Qiuxia Han1, Fengmin Shao2(), Guangyan Cai1, Xiangmei Chen1, Hanyu Zhu1()
1. Department of Nephrology, Chinese People’s Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Beijing 100853, China
2. Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People’s Hospital (Zhengzhou University People’s Hospital), Zhengzhou 450003, China
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Abstract

Netrin-1, an axon guidance factor, and its receptor UNC5B play important roles in axonal development and angiogenesis. This study examined netrin-1 and UNC5B expression in kidneys with diabetic kidney disease (DKD) and investigated their roles in angiogenesis. Netrin-1 and UNC5B were upregulated in streptozotocin-induced DKD Wistar rats, and their expression was compared with that in healthy controls. However, exogenous netrin-1 in UNC5B-depleted human renal glomerular endothelial cells (HRGECs) inhibited cell migration and tubulogenesis. This effect was likely associated with SRC pathway deactivation. Netrin-1 treatment also eliminated the pro-angiogenic effects of exogenous VEGF-165 on UNC5B-silenced HRGECs. These results indicate that UNC5B antagonizes netrin-1 and that UNC5B upregulation contributes partly to enhancing angiogenesis in DKD. Therefore, introducing exogenous netrin-1 and depleting endogenous UNC5B are potential strategies for reducing the incidence of early angiogenesis and mitigating kidney injury in DKD.
Keywords netrin-1      VEGF-165      UNC5B      angiogenesis      diabetic kidney disease     
Corresponding Author(s): Fengmin Shao,Hanyu Zhu   
Just Accepted Date: 28 October 2019   Online First Date: 25 December 2019    Issue Date: 08 June 2020
 Cite this article:   
Xiaojing Jiao,Dong Zhang,Quan Hong, et al. Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease[J]. Front. Med., 2020, 14(3): 293-304.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0715-7
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I3/293
Fig.1  (A) CD31 was upregulated in DN Wistar rat glomeruli. CD31, an endothelial cell marker (Cy3-conjugated, red), was upregulated in DN Wistar rat kidneys compared with its expression in the controls. (B, C) Differential expression of netrin-1 receptors. (B) Netrin-1 receptor levels were quantified in HRGECs via qPCR, with b-actin as the internal control. The data represent 35 amplification cycles. UNC5B and neogenin were abundantly expressed, while UNC5D and UNC5A were barely detected. (C) The bar graph shows the relative expression of each receptor. The results are representative of three independent experiments. (D, E) High glucose level induced UNC5B expression in HRGECs. (D) HRGECs were treated with high (30 mmol/L; HG) or normal (5.5 mmol/L; NG) glucose levels or normal glucose levels with mannitol (5.5 mmol/L glucose and 24.5 mmol/L mannitol; MN) at 37 °C in 5% CO2 atmosphere for 36–48 h. The cells were stained for UNC5B (red), and the nuclei were stained with DAPI (blue). (E) Western blot results show UNC5B expression in HRGECs treated with high (30 mmol/L; HG) or normal (5.5 mmol/L; NG) glucose levels or normal glucose levels with mannitol (5.5 mmol/L glucose and 24.5 mmol/L mannitol; MN) at 37 °C in 5% CO2 atmosphere for 36–48 h. (F) The bar graph shows the relative expression of UNC5B (*P<0.05). The results are representative of three independent experiments.
Dependent variables Control (n = 41) Patients (n = 42) P value
Female sex, n (%)a 16 (39) 9 (21) 0.082
Age (year)b 55.5±11.9 50.3±8.2 0.108
Hypertension, n (% yes)a 16 (39) 20 (48) 0.184
Smoking, n (% yes)a 19 (46) 21 (50) 0.822
Cardiovascular history, n (% yes)a 8 (20) 10 (24) 0.348
BMI (kg/m2)b 22.0±3.2 27.2±3.9 0.408
eGFR (mL/(min·1.73 m2))b 87.9±19.0 72.1±22.9 <0.001
24 h urinary albumin (g/24 h)b 0.207±0.199 3.611±1.687 <0.001
Blood albumin (g/L)b 35.0±5.7 45.0±2.4 <0.001
HbA1c, % mean±SDb 4.46±0.95 7.34±1.73 0.008
Fasting blood glucose (mmol/L)b 4.2±0.5 7.5±2.8 <0.001
Serum creatinine (µmol/L)c 72 (45, 117) 156 (66, 430) <0.001
Serum uric acid (mmol/L)b 313.0±94.1 372.0±68.3 0.083
TC (mmol/L)b 4.18±0.96 5.22±1.27 0.221
TGs (mmol/L)b 0.94±0.44 1.94±0.95 0.004
HDL-c (mmol/L)b 1.45±0.34 1.05±0.28 0.132
LDL-c (mmol/L)b 2.48±0.80 3.32±1.08 0.228
Urine netrin-1 (pg/mL)c 407 (143, 1976) 767 (246, 2300) 0.011
Tab.1  Clinical and biochemical characteristics of DKD patients and normal controls
Fig.2  UNC5B was upregulated in DN patients and DN Wistar rat kidneys. (A) UNC5B was abundantly expressed in human kidney glomeruli and upregulated in the kidneys of DN patients compared with that in patients with MCN. (B) UNC5B was upregulated in STZ-induced DN Wistar rat kidneys compared with that in the control group (CTRL). (C) UNC5B (FITC-conjugated, green) was expressed in the renal cortex microvascular endothelial cells of DN Wistar rats. CD31 (Cy3-conjugated, red) was used as a marker for peritubular and glomerular capillary endothelial cells. The nuclei were stained with DAPI.
Fig.3  Netrin-1 inhibited HRGEC migration and tubulogenesis, and UNC5B antagonized this effect. (A) Western blot results showed efficient UNC5B silencing via specific siRNA. (B) Quantification of relative UNC5B levels in HRGECs. The data represent mean±SD from three independent experiments (*P <0.05). (C) Cell migration assay. VEGF-165 promoted endothelial cell migration in si-UNC5B HRGECs and resulted in faster wound closure. Netrin-1 inhibited wound closure compared with the untreated controls. The effects of VEGF-165 on cell migration were attenuated by pretreatment with netrin-1. VEGF-165 exerted the same effect on si-NC as that on si-UNC5B HRGECs. (D) Histogram showing the relative numbers of migrating cells (*P <0.05). The results are representative of three independent experiments. (E) Tubulogenesis assay. si-UNC5B HRGECs and controls (si-NC) were pretreated with netrin-1 for 6 h before culturing in control medium or medium with VEGF-165. Netrin-1 reduced tubulogenesis in si-UNC5B HRGECs compared with that in the untreated controls and the cells treated with VEGF-165. VEGF-165 promoted tubulogenesis, and netrin-1 antagonized this effect in si-UNC5B, but not in si-NC HRGECs.
Fig.4  Effects of netrin-1 and UNC5B on the expression of VEGFR and its important downstream targets (AKT, SRC, and ERK) in HRGECs. (A) Western blot results showed that netrin-1 inactivated SRC in si-UNC5B HRGECs treated with or without VEGF-165 but had no effect on p-VEGFR, p-AKT, or p-ERK levels. si-NC HRGEC pretreatment with netrin-1 did not affect the activation of any measured proteins. (B) Quantification of relative p-SRC levels in HRGECs. The data represent the mean±SD from three independent experiments.
Fig.5  PP2 inhibited cell migration in si-UNC5B HRGECs. (A, B) Western blot results showed p-SRC downregulation in PP2-treated si-UNC5B HRGECs (*P<0.05). The results are representative of three independent experiments. (C, D) PP2 or netrin-1 treatment inhibited si-UNC5B HRGEC migration (*P<0.05 vs. CTRL group+ VEGFR-165 group). The results are representative of three independent experiments.
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