Abstract: TH-PO498
Semaphorin 3A Inhibitor Ameliorates Renal Fibrosis in Unilateral Ureter Obstruction Mice
Session Information
- CKD: Mechanisms - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Sang, Yizhen, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Tsuji, Kenji, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Fukushima, Kazuhiko, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Kitamura, Shinji, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Wada, Jun, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Background
Renal fibrosis is the common pathological pathway of progressive renal diseases. Semaphorin3A (SEMA3A) is a secreted protein involves in angiogenesis, cell motility and immune cell regulation. Previous reports suggest SEMA3A accelerates renal injury. However, it is unclear whether SEMA3A signaling is associated with renal fibrosis. Here we examined the role of SEMA3A on renal fibrosis using unilateral ureter obstruction (UUO) mouse model and examined the effects of SEMA3A-inhibitor (SEMA3A-I: provided from Dainihon Sumitomo Pharm).
Methods
10-week old wild-type male C57BL/6N mice were assigned into three groups (n=5 / each): UUO group (UUO+daily saline injection), UUO+SEMA3A-I group (UUO+daily SEMA3A-I injection) and sham group. All the mice were sacrificed 2 weeks after UUO surgery. We analyzed the effect of SEMA3A-I in Vivo and in Vitro, using mouse proximal tubular cells (mProx24 cells). In addition, human samples of urine, serum and kidneys from biopsied patients (n=36) were collected to analyze the involvement of SEMA3A in renal diseases.
Results
The expressions of SEMA3A and the receptor, neuropilin-1 (NRP1) increased in renal fibrotic area in UUO group while SEMA3A-I significantly ameliorated UUO-induced renal fibrosis in Masson staining as well as tubular cell apoptosis in TUNEL staining. The expression of phospho-c-Jun, a downstream of c-Jun N-terminal kinase (JNK) signaling, known as the target of SEMA3A-NRP1 signaling, increased in UUO group compared to sham group. In vitro study, the treatment with SEMA3A in mProx24 cells caused Epithelial-Mesenchymal Transition (EMT) with the increase of Vimentin/E-cadherin ratio as well as apoptosis, while SEMA3A-I treatment partially attenuated cisplatin-induced tubular cell apoptosis and TGFβ1-induced EMT. JNK inhibitor decreased SEMA3A-induced tubular apoptosis and EMT. These data suggest that SEMA3A causes renal injury via JNK signaling. The analysis of human data revealed the positive correlation between urinary SEMA3A and N-acetyl-β-D-glucosaminidase (r=0.531, p=0.007). In addition, the higher expression of SEMA3A in tubulointerstitial area were seen in human kidneys with severe renal fibrosis, confirming SEMA3A signaling is associated with tubular injury and fibrosis.
Conclusion
SEMA3A-I ameliorates UUO-induced renal fibrosis and tubular injury through the inhibition of JNK signaling.
Funding
- Government Support - Non-U.S.