Semaporin3A inhibitor ameliorates renal fibrosis through the regulation of JNK signaling

Yizhen Sang, Kenji Tsuji, Kazuhiko Fukushima, Kensaku Takahashi, Shinji Kitamura, Jun Wada

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)F740-F756
JournalAmerican Journal of Physiology - Renal Physiology
Volume321
Issue number6
DOIs
Publication statusPublished - Dec 2021

Keywords

  • C-Jun NH-terminal kinase
  • Myofibroblast
  • Renal fibrosis
  • Semaphorin3A

ASJC Scopus subject areas

  • Physiology
  • Urology

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