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Chronic Salmonella Infection Induced Intestinal Fibrosis
Published on: September 22, 2019
Proximal Tubule-Derived Semaphorin 3C Promotes Fibrosis in Adenine-Induced Tubulointerstitial Nephritis
Tomohiro Takehara1, Yoichiro Otaki1, Kazunobu Ichikawa1
1Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
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 (Ndrg1CreERT2/+; Sema3cflox/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+/+; Sema3cflox/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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