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C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis
Runhong Han, … , Zhihong Liu, Hao Bao
Runhong Han, … , Zhihong Liu, Hao Bao
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e122912. https://doi.org/10.1172/jci.insight.122912.
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Research Article Nephrology

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

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Abstract

Chronic tubulointerstitial injury impacts the prognosis of focal segmental glomerulosclerosis (FSGS). We found that the level of versican V1 was increased in tubular cells of FSGS patients. Tubular cell–derived versican V1 induced proliferation and collagen synthesis by activating the CD44/Smad3 pathway in fibroblasts. Both urine C3a and suPAR were increased and bound to the tubular cells in FSGS patients. C3a promoted the transcription of versican by activating the AKT/β-catenin pathway. C3aR knockout decreased the expression of versican in Adriamycin-treated (ADR-treated) mice. On the other hand, suPAR bound to integrin β6 and activated Rac1, which bound to SRp40 at the 5′ end of exon 7 in versican pre-mRNA. This binding inhibited the 3′-end splicing of intron 6 and the base-pair interactions between intron 6 and intron 8, leading to the formation of versican V1. Cotreatment with ADR and suPAR specifically increased the level of versican V1 in tubulointerstitial tissues and caused more obvious interstitial fibrosis in mice than treatment with only ADR. Altogether, our results show that C3a and suPAR drive versican V1 expression in tubular cells by promoting transcription and splicing, respectively, and the increases in tubular cell–derived versican V1 induce interstitial fibrosis by activating fibroblasts in FSGS.

Authors

Runhong Han, Shuai Hu, Weisong Qin, Jinsong Shi, Qin Hou, Xia Wang, Xiaodong Xu, Minchao Zhang, Caihong Zeng, Zhihong Liu, Hao Bao

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Figure 4

C3a induces versican expression in tubular cells of FSGS.

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C3a induces versican expression in tubular cells of FSGS.
(A) RT-PCR ana...
(A) RT-PCR analysis of total versican in tubular cells treated with 20% patient serum (PS), 20% heat-inactivated patient serum (HIPS), 20% healthy serum (HS), or 20% heat-inactivated healthy serum (HIHS) for 48 hours (n = 3). (B) RT-PCR analysis of total versican in tubular cells treated with 20% PS, eculizumab, or SB290157 for 48 hours (n = 5). (C) Level of serum C3a in FSGS patients and controls (n = 20). (D) Level of urinary C3a in FSGS patients and controls (n = 20). (E) Immunofluorescence staining of C3a (red) and C3aR (green) in renal tissue of FSGS patients (n = 3). (F) RT-PCR analysis of total versican, versican V1, V0, and V3 in tubular cells treated with C3a or 20% PS for 48 hours (n = 3). Scale bars: 20 μm. For statistical analysis, 1-way ANOVA with Tukey’s post hoc test was used for A, B, and F, and a 2-tailed Student’s t test was used for C and D. *P < 0.05 compared with control; #P < 0.05 compared with PS-, HS-, or C3a-treated cells.

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