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. 2021 Feb 11:11:575722.
doi: 10.3389/fphys.2020.575722. eCollection 2020.

The Study of Angptl4-Modulated Podocyte Injury in IgA Nephropathy

Sha Jia  1   2   3   4   5   6 , Xiaofeng Peng  1   2   3   4   5 , Ludan Liang  1   2   3   4   5 , Ying Zhang  1   2   3   4   5 , Meng Li  1   2   3   4   5 , Qin Zhou  1   2   3   4   5 , Xiujin Shen  1   2   3   4   5 , Yucheng Wang  1   2   3   4   5 , Cuili Wang  1   2   3   4   5 , Shi Feng  1   2   3   4   5 , Jianghua Chen  1   2   3   4   5 , Pingping Ren  1   2   3   4   5 , Hong Jiang  1   2   3   4   5
Affiliations

The Study of Angptl4-Modulated Podocyte Injury in IgA Nephropathy

Sha Jia et al. Front Physiol. .

Abstract

Background: Increasing evidence shows that Angptl4 affects proteinuria in podocytes injured kidney disease, however, whether there is a relationship between Angptl4 and IgA nephropathy (IgAN) has not been studied yet.

Methods: Plasma and urine samples were obtained from 71 patients with IgAN and 61 healthy controls. Glomeruli from six renal biopsy specimens (three IgAN patients and three healthy controls) were separated by RNA-Seq. Differentially expressed genes (DEGs) related to podocytes and Angptl4 between IgAN patients and healthy controls were performed using the Limma package. Gene set enrichment analysis was used to determine whether there was a statistically significant difference between the two groups. STRING was used to create a protein-protein interaction network of DEGs. Association analysis between Angptl4 levels and clinical features of IgAN was performed.

Results: Thirty-three podocyte-related and twenty-three Angpt4-related DEGs were found between IgAN patients and healthy controls. By overlapping the genes, FOS and G6PC were found to be upregulated in IgAN patients, while MMP9 was downregulated in IgAN patients. Plasma and urine Angptl4 levels were closely related to the degree of podocyte injury and urine protein, but not to the protein-creatine ratio.

Conclusion: Our findings show that Angptl4 levels in plasma and urine are related to podocyte damage and, therefore, may be a promising tool for assessing the severity of IgAN patients to identify and reverse the progression to ESRD.

Keywords: Angptl4; RNA-Seq; immunoglobulin A nephropathy; podocyte; progression.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Heatmaps of differentially expressed genes associated with Angiopoietin-like protein 4 and podocyte injury in IgA nephropathy (IgAN) patients compared to healthy controls. (A) The glomerular expression levels of 33 differentially expressed genes that were previously reported to be related to podocytes. The red areas represent genes expressed at high levels and the blue areas represent genes expressed at low levels in IgAN patients compared with healthy controls. The official gene names and test values of the IgAN patients and the controls are provided. A positive log2 (fold change) indicated upregulation in the disease group, and a negative log2 (fold change) indicated downregulation in the disease group. (B) The glomerular expression levels of 23 differentially expressed genes correlated with Angptl4. Refer to panel (A) for the description of the figure.
FIGURE 2
FIGURE 2
Gene set enrichment analysis of Angiopoietin-like protein 4. (A) The Angptl4 gene participated in 7 enriched sets that were statistically significantly different between the IgA nephropathy (IgAN) group and the control group. (B) The transcripts of three genes, namely, FOS, G6PC, and MMP9, were simultaneously included in the Angptl4-related and podocyte-related genes. Two of these genes, namely, FOS and G6PC, were upregulated in the disease group, whereas MMP9 was downregulated in the disease group. (C) The depiction of the network of Angptl4, FOS, G6PC, and MMP9 with several differentially expressed genes selected from among the Angptl4-related or podocyte-related genes by STRING.
FIGURE 3
FIGURE 3
Angiopoietin-like protein 4 levels in plasma and urine. (A,B) The expression of Angptl4 in plasma and urine was detected in IgA nephropathy (IgAN) without podocyte injury patients (n = 34), IgAN with podocyte injury patients (n = 37), and normal controls (n = 61) by enzyme-linked immunosorbent assay. (C,D) The relationship between urine protein (g/L) and Angptl4 expression in plasma and urine was analyzed in IgAN patients (n = 61). (E,F) The relationship between the urine protein-creatinine ratio (g/g) and Angptl4 expression in plasma and urine was analyzed in IgAN patients (n = 61). The data are expressed as the mean ± SEM. ***P < 0.001 compared with the normal controls.
FIGURE 4
FIGURE 4
Analysis of podocyte foot process effacement in the two patient groups and the control group. (A) Electron microscopy image of no podocyte foot process effacement in the IgA nephropathy (IgAN) patients without podocyte group. (B) Electron microscopy image of podocyte foot process effacement in the IgAN patients with podocyte group (scale bar = 1 or 2 μm). (C,D) The expression of plasma and urinary Angptl4 in IgAN patients with podocyte foot process focal effacement (n = 28), diffuse effacement (n = 9), and controls (healthy and IgAN patients without podocyte injury) (n = 95). The data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with the controls.
See this image and copyright information in PMC

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