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Войти в исследования Kidney360 · 2026
Proximal Tubule‑Derived Semaphorin 3C Promotes Fibrosis in Adenine-Induced Tubulointerstitial Nephritis.
СтатьяНазвание и аннотация: Перевод в очереди
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Takehara Tomohiro, Otaki Yoichiro, Ichikawa Kazunobu, Kuramasu Yuzuka, Ono Hiroe, Yamaguchi Ryuhei, Miyata Masahiro, Koizumi Miho, Watanabe Sayumi, Kamei Keita, Ochi Haruki, Watanabe Tetsu, Yanagita Motoko, Honda Hiroaki, Manabe Ichiro, Watanabe Masafumi
Аннотация
KEY POINTS: Proximal tubule‑derived semaphorin 3C functioned as a promoter of inflammation and fibrosis in adenine-induced tubulointerstitial nephritis. Semaphorin 3C acted on renal fibroblasts to enhance the expression of profibrotic markers and to promote proliferation. Thus, proximal tubule‑derived semaphorin 3C may represent a potential therapeutic target in tubulointerstitial nephritis.
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 CKD remains unclear.
METHODS: We performed immunostaining for SEMA3C in human and murine kidneys. Subsequently, tamoxifen-inducible proximal tubule‑specific Sema3c functional knockout mice ( Ndrg1CreERT2/+ ; Sema3cflox/flox , PT- Sema3c FKO) were generated using the clustered regularly interspaced short palindromic repeats-Cas9 technique. To evaluate the renoprotective effects of PT- Sema3c FKO, we used two well-established models of CKD: the adenine-induced tubulointerstitial nephritis model and high-fat diet/streptozotocin-induced diabetic nephropathy (DN) model.
RESULTS: Immunostaining of human and murine kidneys showed high SEMA3C expression in the proximal tubules (PTs), particularly in human tubulointerstitial nephropathy. In adenine-induced tubulointerstitial nephritis, control (Ctrl) littermates ( Ndrg1+/+ ; Sema3cflox/flox ) showed increased Sema3c expression, whereas PT- Sema3c FKO mice exhibited markedly reduced Sema3c expression with attenuated fibrosis and inflammation. By contrast, in the high-fat diet/streptozotocin-induced DN model, renal Sema3c expression decreased in Ctrl mice after DN induction, and neither proteinuria nor fibrosis was ameliorated in PT- Sema3c FKO mice. In vitro , SEMA3C expression in PT cells was upregulated by TNF- α or TGF- 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.
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 CKD remains unclear.
METHODS: We performed immunostaining for SEMA3C in human and murine kidneys. Subsequently, tamoxifen-inducible proximal tubule‑specific Sema3c functional knockout mice ( Ndrg1CreERT2/+ ; Sema3cflox/flox , PT- Sema3c FKO) were generated using the clustered regularly interspaced short palindromic repeats-Cas9 technique. To evaluate the renoprotective effects of PT- Sema3c FKO, we used two well-established models of CKD: the adenine-induced tubulointerstitial nephritis model and high-fat diet/streptozotocin-induced diabetic nephropathy (DN) model.
RESULTS: Immunostaining of human and murine kidneys showed high SEMA3C expression in the proximal tubules (PTs), particularly in human tubulointerstitial nephropathy. In adenine-induced tubulointerstitial nephritis, control (Ctrl) littermates ( Ndrg1+/+ ; Sema3cflox/flox ) showed increased Sema3c expression, whereas PT- Sema3c FKO mice exhibited markedly reduced Sema3c expression with attenuated fibrosis and inflammation. By contrast, in the high-fat diet/streptozotocin-induced DN model, renal Sema3c expression decreased in Ctrl mice after DN induction, and neither proteinuria nor fibrosis was ameliorated in PT- Sema3c FKO mice. In vitro , SEMA3C expression in PT cells was upregulated by TNF- α or TGF- 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.