C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis

Han, Ruiming; Zhou, Tianjun; Qin, Weisong; Shi, Jin‐Song; Hou, Qingwen; Wang, Xia; Xu, Xiaodong; Zhang, Minchao; Zeng, Caihong; Liu, Zhihong; Bao, Hanying

doi:10.1172/jci.insight.122912

Cited by 28 publications

(21 citation statements)

References 68 publications

(75 reference statements)

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“…XAV-939, a selective inhibitor to Wnt/β-catenin signaling pathway by tankyrase1/2 inhibition (14,35), could upregulate the expression of CNPase, PLP, MBP, MAG, CC1, Olig1, Olig2 and SOX10 and decrease the expression of NG2 in OPCs treated with C3a. As reported by Han, C3a could lead to a significant phosphorylation of AKT and the nuclear accumulation of β-catenin in tubular cells (33). Phosphorylated AKT can activate β-catenin/TCF4 transcriptional activity by the indirect stabilization of β-catenin through GSK-3β inhibition and by directly inhibiting the phosphorylation of β-catenin (53).…”

Section: Discussionmentioning

confidence: 82%

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Huang

Zhang

Lin³

et al. 2019

Brain Pathology

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Neuroinflammation is thought to play a pivotal role in the pathogenesis of periventricular white matter (PWM) damage (PWMD) induced by neonatal sepsis. Because the complement cascade is implicated in inflammatory response, this study was carried out to determine whether C3a is involved in PWMD, and, if so, whether it would induce axonal hypomyelination. Furthermore, we explored if C3a would act through its C3a receptor (C3aR) and thence inhibit maturation of oligodendrocyte precursor cells (OPCs) via the WNT/β-catenin signal pathway. Sprague Dawley (SD) rats aged 1 day were intraperitoneally injected with lipopolysaccharide (LPS) (1 mg/ kg). C3a was upregulated in activated microglia and astrocytes in the PWM up to 7 days after LPS injection. Concomitantly, enhanced C3aR expression was observed in NG2 + oligodendrocytes (OLs). Myelin proteins including CNPase, PLP, MBP and MAG were significantly reduced in the PWM of 28-day septic rats. The number of PLP + and MBP + cells was markedly decreased. By electron microscopy, myelin sheath thickness was thinner and the average g-ratios were higher. This was coupled with an increase in number of NG2 + cells and decreased number of CC1 + cells. Olig1, Olig2 and SOX10 protein expression was significantly reduced in the PWM after LPS injection. Very strikingly, C3aRa administration for the first 7 days could reverse the above-mentioned pathological alterations in the PWM of septic rats. When incubated with C3a, expression of MBP, CNPase, PLP, MAG, Olig1, Olig2, SOX10 and CC1 in primary cultured OPCs was significantly downregulated as opposed to increased NG2. Moreover, WNT/β-catenin signaling pathway was found to be implicated in inhibition of OPCs maturation and differentiation induced by C3a in vitro. As a corollary, it is speculated that C3a in the PWM of septic rats is closely associated with the disorder of OPCs differentiation and maturation through WNT/β-catenin signaling pathway, which would contribute ultimately to axonal hypomyelination. Huang et al C3a induces hypomyelination in the septic brain

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Section: Discussionmentioning

confidence: 82%

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Huang

Zhang

Lin³

et al. 2019

Brain Pathology

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“…V2 is only expressed in the central neuron system ( Wight et al, 2014a , b ; Wight, 2017 ). In previous studies of CKD, versican has been discovered as a predictor of disease progression, but there is no study focusing on the influence of versican on DKD tubulointerstitium ( Rudnicki et al, 2012 ; Han et al, 2019 ; Taylor et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of VCAN as Hub Gene for Diabetic Kidney Disease Immune Injury Using Integrated Bioinformatics Analysis

Wang

et al. 2021

Front. Physiol.

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Background: Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease in China. Tubular injury contributes to the progression of DKD. Our study was conducted to explore the differential gene expression profiles between kidneys from patients with DKD and kidney living donors (LDs).Methods: In total, seven DKD and eighteen LD gene expression profiles from the GSE104954 dataset were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were analyzed in R with the limma package. DEGs were uploaded to the g:Profiler online database to explore the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Ingenuity pathway analysis (IPA) was carried out using online IPA software. Weighted gene co-expression network analysis (WGCNA) was performed using the WGCNA R package. By integrating DEGs and genes from the top 1 phenotype-gene associated module, we determined the hub gene. We next tested the hub gene, VCAN, in the GSE30122 dataset. We also validated the versican levels in human kidney tissues, explored immune cell type enrichment using an online database xCell, and investigated the correlation between cell types and VCAN expression.Results: A total of 563 DEGs was identified. A large number of pathways were involved in the immune response process according to the results of GO, KEGG, and IPA. Using WGCNA, we selected the lightcyan module in which genes showed the strongest correlation with the phenotype and smallest P-value. We also identified VCAN as a hub gene by integrating DEG analysis and WGCNA. Versican expression was upregulated in human diabetic kidney tissue. Moreover, versican was speculated to play a role in immune injury according to the enrichment of functions and signaling pathways. VCAN transcript levels correlate with the assembly of immune cells in the kidney.Conclusion: Immune processes played an essential role in DKD tubulointerstitium injury. The hub gene VCAN contributed to this process.

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“…As C57BL/6 mice are resistant to ADR-induced nephropathy ( Lee and Harris, 2011 ), ADR nephropathy was induced by injection of 10.5 mg/kg ADR (D1515; Sigma-Aldrich) via the tail vein in BALB/c male mice at age 10–12 wk ( Han et al, 2019 ), and mice were sacrificed at 4 wk after injection. DN was induced in C57BL/6 male mice aged 8 wk by intraperitoneal injection with streptozotocin (STZ; 50 µg/g; S0130; Sigma-Aldrich) for 5 d consecutively.…”

Section: Methodsmentioning

confidence: 99%

Upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes

Zhou

Han

Chen

et al. 2020

Journal of Experimental Medicine

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Podocyte injury is a common hallmark in various glomerular diseases. The level of LRRC55 was increased in podocytes of patients with focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN), and membranous nephropathy (MN). Upregulated LRRC55 and increased intracellular Ca2+ led to BK channel activation and the loss of intracellular potassium, resulting in apoptosome formation and caspase-3 activation in angiotensin II (Ang II)–treated podocytes. Knockout of Lrrc55 or the BK channel prevented the BK current and ameliorated podocyte injury in Ang II–treated mice. Upstream, NFATc3 regulated the expression of LRRC55. Increased LRRC55 expression in podocytes was also evident in animal models of FSGS, DN, and MN. Treatment with losartan or LRRC55 siRNA suppressed LRRC55 expression, prevented BK channel activation, and attenuated podocyte injury in animal models of FSGS, DN, and MN. In conclusion, upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes in FSGS, DN, and MN. LRRC55 inhibition may represent a new therapeutic approach for podocyte injury.

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C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis

Cited by 28 publications

References 68 publications

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Identification of VCAN as Hub Gene for Diabetic Kidney Disease Immune Injury Using Integrated Bioinformatics Analysis

Upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes

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