DOI: 10.34067/kid.0000001242 ISSN: 2641-7650

Proximal Tubule-Derived Semaphorin 3C Promotes Fibrosis in Adenine-Induced Tubulointerstitial Nephritis

Tomohiro Takehara, Yoichiro Otaki, Kazunobu Ichikawa, Yuzuka Kuramasu, Hiroe Ono, Ryuhei Yamaguchi, Masahiro Miyata, Miho Koizumi, Sayumi Watanabe, Keita Kamei, Haruki Ochi, Tetsu Watanabe, Motoko Yanagita, Hiroaki Honda, Ichiro Manabe, Masafumi Watanabe
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Background:

Semaphorin 3C (SEMA3C) is a secreted protein that is essential for cardiovascular and renal development; however, its role in the development and progression of chronic kidney disease (CKD) remains unclear.

Methods:

We performed immunostaining for SEMA3C in human and murine kidneys. Subsequently, tamoxifen-inducible proximal tubule (PT)-specific Sema3c functional knockout (FKO) mice ( Ndrg1 CreERT2/+ ; Sema3c flox/flox , PT- Sema3c FKO) were generated using the CRISPR–Cas9 technique. To evaluate the renoprotective effects of PT- Sema3c FKO, we employed two well-established models of CKD: the adenine-induced tubulointerstitial nephritis model and the high-fat diet (HFD)/streptozotocin-induced diabetic nephropathy (DN) model.

Results:

Immunostaining of human and murine kidneys showed high SEMA3C expression in the PTs, particularly in human tubulointerstitial nephropathy. In adenine-induced tubulointerstitial nephritis, control ( Ctrl ) littermates ( Ndrg1 +/+ ; Sema3c flox/flox ) showed increased Sema3c expression, whereas PT- Sema3c FKO mice exhibited markedly reduced Sema3c expression with attenuated fibrosis and inflammation. In contrast, in HFD/streptozotocin-induced DN model, renal Sema3c expression decreased in Ctrl mice following DN induction, and neither proteinuria nor fibrosis was ameliorated in PT- Sema3c FKO mice. In vitro , SEMA3C expression in PT cells was upregulated by tumor necrosis factor-α or transforming growth factor-β; however, it was downregulated under glucotoxic conditions. SEMA3C stimulation of kidney fibroblasts induced profibrotic marker expression and proliferation.

Conclusions:

PT-derived SEMA3C promotes inflammation and fibrosis in adenine-induced tubulointerstitial nephritis.

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