TY - JOUR
T1 - Semaporin3A inhibitor ameliorates renal fibrosis through the regulation of JNK signaling
AU - Sang, Yizhen
AU - Tsuji, Kenji
AU - Fukushima, Kazuhiko
AU - Takahashi, Kensaku
AU - Kitamura, Shinji
AU - Wada, Jun
N1 - Funding Information:
This work was supported by China Scholarship Council Grant 201708210186 (to Y.S.), Japanese Society for the Promotion of Science (JSPS)/Grants-in-Aid for Young Scientists 18K15978 and 20K17283 (to K.T.), The Yukiko Ishibashi Foundation (to K.T.), The Sanyo Broadcasting Foundation (to K.T.), Japanese Association of Dialysis Physicians Grant 2019-9 (to K.T.), a grant for the pathophysiological research conference in chronic kidney disease (Grant JKFB19-4, to K.T.), and JSPS/Grant-in-Aid for Scientific Research 18K08244 (to S.K.).
Publisher Copyright:
Copyright © 2021 the American Physiological Society.
PY - 2021/12
Y1 - 2021/12
N2 - Renal fibrosis is the common pathological pathway in progressive renal diseases. In the present study, we analyzed the roles of semaphorin 3 A (SEMA3A) on renal fibrosis and the effect of SEMA3A inhibitor (SEMA3A-I) using a unilateral ureteral obstruction (UUO) mouse model. Expression of SEMA3A in the proximal tubulus and neuropilin-1, a recepor of SEMA3A, in fibloblast and tubular cells were increased in UUO kidneys. The expression of myofibroblast marker tenascin-C and fibronection as well as renal fibrosis were increased in UUO kidneys, all of which were ameliorated by SEMA3A-I. In addition, the JNK signaling pathway, known as the target of SEMA3A signaling, was activated in proximal tubular cells and fibroblast cells after UUO surgery, and SEMA3A-I significantly attenuated the activation. In vitro, treatments with SEMA3A as well as transforming growth factor-b1 (TGF-b1) in human proximal tubular cells lost epithelial cell characteristics, and SEMA3A-I significantly ameliorated this transformation. The JNK inhibitor SP600125 partially reversed SEMA3A and TGF-b1-induced cell transformation, indicating that JNK signaling is involved in SEMA3A-induced renal fibrosis. In addition, treatment with SEMA3A in fibroblast cells activated expression of tenascin-C, collagen type I, and fibronection, indicating that SEMA3A may accelerate renal fibrosis through the activation of fibroblast cells. Analysis of human data revealed the positive correlation between urinary SEMA3A and urinary N-acetyl-b-D-glucosaminidase, indicating the association between SEMA3A and tubular injury. In conclusion, SEMA3A signaling is involved in renal fibrosis through the JNK signaling pathway and SEMA3A-I might be a therapeutic option for protecting from renal fibrosis.
AB - Renal fibrosis is the common pathological pathway in progressive renal diseases. In the present study, we analyzed the roles of semaphorin 3 A (SEMA3A) on renal fibrosis and the effect of SEMA3A inhibitor (SEMA3A-I) using a unilateral ureteral obstruction (UUO) mouse model. Expression of SEMA3A in the proximal tubulus and neuropilin-1, a recepor of SEMA3A, in fibloblast and tubular cells were increased in UUO kidneys. The expression of myofibroblast marker tenascin-C and fibronection as well as renal fibrosis were increased in UUO kidneys, all of which were ameliorated by SEMA3A-I. In addition, the JNK signaling pathway, known as the target of SEMA3A signaling, was activated in proximal tubular cells and fibroblast cells after UUO surgery, and SEMA3A-I significantly attenuated the activation. In vitro, treatments with SEMA3A as well as transforming growth factor-b1 (TGF-b1) in human proximal tubular cells lost epithelial cell characteristics, and SEMA3A-I significantly ameliorated this transformation. The JNK inhibitor SP600125 partially reversed SEMA3A and TGF-b1-induced cell transformation, indicating that JNK signaling is involved in SEMA3A-induced renal fibrosis. In addition, treatment with SEMA3A in fibroblast cells activated expression of tenascin-C, collagen type I, and fibronection, indicating that SEMA3A may accelerate renal fibrosis through the activation of fibroblast cells. Analysis of human data revealed the positive correlation between urinary SEMA3A and urinary N-acetyl-b-D-glucosaminidase, indicating the association between SEMA3A and tubular injury. In conclusion, SEMA3A signaling is involved in renal fibrosis through the JNK signaling pathway and SEMA3A-I might be a therapeutic option for protecting from renal fibrosis.
KW - C-Jun NH-terminal kinase
KW - Myofibroblast
KW - Renal fibrosis
KW - Semaphorin3A
UR - http://www.scopus.com/inward/record.url?scp=85120607121&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120607121&partnerID=8YFLogxK
U2 - 10.1152/AJPRENAL.00234.2021
DO - 10.1152/AJPRENAL.00234.2021
M3 - Article
C2 - 34747196
AN - SCOPUS:85120607121
SN - 0363-6127
VL - 321
SP - F740-F756
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 6
ER -
